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Archive for the ‘Anxiety’ Category

Phillip Seymour Hoffman did not have choice or free will and neither do you.

In ADHD, Anxiety, Brain imaging, Brain studies, Child/Adolescent Psychology, General Psychology, Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry on Tuesday, 11 March 2014 at 12:37

one of the best things about this subject that i’ve read in a long time.  give it a read. it makes you think.

Phillip Seymour Hoffman did not have choice or free will and neither do you..

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stop anxiety

In Anxiety, Mindfulness on Friday, 3 May 2013 at 06:02

Stop Anxiety In It’s Tracks

Michael S. Broader, Ph.D.

Believe it or not, fear can be a good thing. If our ancestors didn’t feel fear and react to it properly, they wouldn’t have protected themselves when they saw a dangerous predator coming after them, and we would not have survived. Thus, the survival mechanism of fear has thankfully survived, or the human species would not have. In our modern society, we rarely — but sometimes — need our fear responses to save our lives, such as when a dangerous person meaning harm is stalking us. Nevertheless, when this happens, we can fortunately use the fear response to fight or flee.

Physiologically, anxiety is identical to fear, resulting in symptoms that may include shortness of breath, sweating, blushing, muscle weakness or tension, butterflies in your stomach, or constriction of the throat and chest. Fear, however, is about something specific that usually makes it rational, appropriate, and helpful in many ways. Anxiety on the other hand, is not connected to any real danger or life-threatening event. Anxiety — as opposed to fear — generally stifles you from taking any action and sometimes causes you to avoid things you wish you could do. Oftentimes, anxiety provokes feelings of shame, while fear is rarely shameful, as it is a protective mechanism. Whether yours is minor worrying or more severe (such as feelings of panic or losing control), if you experience your anxiety as interfering with your ability to function in your daily life, it might be time to take some steps to get it under control. While you may not be able to control what’s happening with the people, places and things around you, you can absolutely learn to control yourreaction to an external event.

What specific things in your life trigger anxiety? Make a list of the things that trigger you on a regular basis. It can be helpful to write down events that occurred the past week that might have set off your anxious feelings. (My book Stage Climbing: The Shortest Path to Your Highest Potential can be a good resource to help you recognize what makes you anxious in the big picture.) Using one item from your list, think about these questions to figure out what you’re telling yourself that may have created your anxiety and then to challenge your thinking. When this situation occurred, what thoughts were you having? What feelings or emotions did you experience? What were you telling yourself at the time? Were you in any real danger? What is the worst thing that could possibly happen to you as a result of the event. Finally, how likely is it that this worst thing will happen?

For example, if you felt anxious when your boss called you into his office, maybe you had the thought that you were going to be fired. It’s possible that you then felt nervous and helpless. Perhaps you told yourself “I won’t ever find another job and therefore I won’t be able to support myself or my family.” In this case, while being laid off might be extremely stressful, it’s not life threatening. If your mind tends to jump to the irrational worst-case scenario, like having to live on the street, this is your anxiety talking, since chances are it’s probably quite unlikely that would happen. Begin to practice writing these questions and answers down as you experience anxiety-provoking situations throughout your week, and/or try this exercise with other items on your list.

What can you tell yourself instead of those things that create and worsen your anxiety? What are some new ways to think about them? A good question to ask yourself is what is a more realistic, rational attitude I could substitute in this situation? For example, if you think you’re going to be fired, you can consider that your boss might have a question for you or even want to praise you for your work. And even if the worst scenario becomes reality, where’s the evidence that you can’t survive it? When you look at your list at a later point after the anxiety has subsided, ask yourself, what does my irrational side say and what does my rational side say? Can I choose to listen to my rational side instead?

Ask yourself what you’d advise someone else whom you cared about do with similar thoughts. If another person thought they’d be fired because they were called into a meeting or that if they were fired, it would be catastrophic, would you agree? If you’re able to think about it rationally for someone else, you can certainly do so for yourself. Another option is to say STOP to yourself aloud or silently when you begin to have worrisome thoughts. While this may seem silly, this simple technique can help shift your attention in the moment away from worrying.

Once you are aware of those things that trigger anxiety, it’s helpful to have a “to do” list on hand you for when you begin to worry. For example, when anxious feelings start, one simple strategy you can try is a deep breathing exercise. Imagine your legs are two giant air balloons. As you inhale, imagine your legs filling up with air. As you exhale, imagine all of the air leaving your body. Try this, breathing in to the count of five and out to the five as many times as necessary to feel the anxiety dissipate.

If you can’t seem to reduce your anxiety, ask yourself if there is purpose your anxiety is serving. Maybe your anxiety keeps you in a relationship or at a job that you’re afraid to leave. If so, face those issues head on, until you are operating according to your choices — not your anxiety!

As you try these various techniques, notice which ones work best for you. The more you practice a particular strategy, the easier it becomes to gain mastery over your anxiety. Feeling more relaxed something you can achieve. If your anxiety continues to affect your life negatively, I encourage you to seek professional help.

For more action steps to reduce your anxiety, download my complimentary audio programOvercoming Your Anxiety.

For more by Michael S. Broder, Ph.D., click here.

For more on emotional wellness, click here.

Retrieved from: http://www.huffingtonpost.com/michael-s-broder-phd/anxiety-tips_b_3177592.html

wired for anxiety?

In Anxiety, Child/Adolescent Psychology, General Psychology, Psychiatry, School Psychology on Sunday, 10 February 2013 at 08:31

Are We All Just Wired for Anxiety?

By: Ben Michaels, Ph.D.

 Michael Shermer’s TEDTalk, “The Pattern Behind Self-deception” is both groundbreaking and earth-shattering. The neuroscience Shermer cites in his talk is tight, his examples are strong and his conclusions far-reaching. The implications that many have drawn from his talk regarding larger belief systems are beyond my expertise as a clinical psychologist and so I will (wisely or cowardly — you choose) sidestep these arguments.

I do however, think that one of the factors that Dr. Shermer stumbles upon in his talk has a wide applications for the field of clinical psychology, which is this:

If Shermer is right (and he is), and that our default setting is to see patterns where they don’t exist because the cost of being wrong (that there is no pattern) is usually much higher than the cost of being right (that there is a pattern) then I have some bad news for you:

We are all just wired for anxiety.

Let me break it down:

Let’s say something bad happens to us: We have a breakup, a breakdown, a trauma, an insult or injury of any kind. This leads us to seek out patterns in our environments that could signify the possibility of future pain. In fact, Shermer says that when we feel uncertain (like after a trauma) we will be even more prone to seeking out patterns, possibly seeing them where they don’t exist.

This desperate pattern seeking is, in essence, the pernicious spiral of anxiety: We are afraid of what’s next so our minds exit the present to try to solve an unsolveable math problem about our futures. The reason the problem is unsolveable is that all of the variables don’t yet exist. The key variable being the actual event.

If this tendency is our natural weakness, we must overcome it by using our natural strength: Thinking and testing our beliefs.

For example, I once worked with a handsome young man, who we will call, Nate, who was constantly told that he was “ugly” and “stupid” by his abusive father. When he first came to me, Nate was convinced that no woman would ever want to date him, let alone, marry him.

I responded to him by saying, maybe he’s right maybe no woman would have him, but there is only one way to find out: test his beliefs in the real world. I told him that if he asked out all the women in the world and none of them want to date him, than his anxiety would be justified If at least one woman wanted to then it would not be.

He realized that this was absurd, but after a great deal of relentless pushing, Nate agreed to try to approach a few women over time.

Fourteen months later he was engaged. He is now happily married and currently expecting his third child.

Science/Empiricism = 1; Anxiety/Fear = 0

The takeaway is this: We may indeed be wired for anxiety, but that does not mean that anxiety is our fate. If we use the gift of our minds well, we can overcome our wiring.

If you read this and are feeling anxious or are buried under the weight of any false belief because of your wiring, do the hard thing: Test it out. The only thing you have to lose is your anxiety!

Ideas are not set in stone. When exposed to thoughtful people, they morph and adapt into their most potent form. TEDWeekends will highlight some of today’s most intriguing ideas and allow them to develop in real time through your voice! Tweet #TEDWeekends to share your perspective or emailtedweekends@huffingtonpost.com to learn about future weekend’s ideas to contribute as a writer.

Retrieved from: http://www.huffingtonpost.com/ben-michaelis-phd/wired-for-anxiety_b_2599944.html?utm_source=linkedin&utm_medium=social&utm_content=2c773f97-31e5-4b88-bbb2-fa255a762ed1

Click here to read the original op-ed from the TED speaker who inspired the post and watch the TEDtalk below:

http://www.huffingtonpost.com/michael-shermer/what-is-skepticism-anyway_b_2581917.html?ir=TED+Weekends&ref=topbar

 

Depression, Other Psychosocial Disorders Linked to Stroke

In Anxiety, Mood Disorders, Well-being on Friday, 14 December 2012 at 08:35

Depression, Other Psychosocial Disorders Linked to Stroke

Pauline Anderson

Older adults who are depressed, stressed, or dissatisfied with their life are at increased risk of suffering a stroke and of dying from a stroke, a new study has found.

The study showed that those who faced the highest level of psychosocial distress had a significantly increased risk of having a stroke and up to 3 times the risk of stroke mortality compared with those with the least amount of distress.

“Our findings clearly document important adverse effects of psychosocial distress on cerebrovascular disease risk in the elderly,” write the authors, including senior author Susan Everson-Rose, PhD, associate professor of medicine and associate director of the Program in Health Disparities Research, University of Minnesota, Minneapolis.

The study is published online December 13 in Stroke.

Distress Score

The study used data from the Chicago Health and Aging Project (CHAP), an ongoing, longitudinal study investigating chronic illnesses in elderly residents of 3 adjacent neighborhoods in Chicago, who represent a broad range of socioeconomic backgrounds. Researchers conducted baseline interviews to gather information on medical history, cognitive health, socioeconomic status, behavioral patterns, and psychosocial characteristics, repeating the interviews in 3-year cycles.

The second cycle of interviews (1997 to 1999) assessed the broadest range of psychosocial characteristics and served as the baseline for the current analysis, which included 4120 mostly black and female participants whose average age was 77 years. Most had a high school education and an average of 1 chronic condition; 13.1% reported a history of stroke.

For information on stroke hospitalizations, researchers accessed the Centers for Medicare and Medicaid Services Medicare Claims data (because some participants were involved in a health maintenance organization, only 2649 participants were analyzed for rates of incident stroke). To verify deaths, the authors used linkages with the National Death Index.

To assess psychosocial distress, investigators created a distress score that factored in 4 psychosocial measures: depressive symptoms, perceived stress, neuroticism (a personality domain characterized by anxious, angry, and vulnerable traits), and life satisfaction. The higher the score is, the higher the distress.

The study showed a dose-response pattern of risk for incident stroke. Relative to the least distressed quartile, the hazard ratios (HRs) for the second, third, and fourth quartiles were 1.27 (95% confidence interval [CI], 0.98 – 1.65; P = .067), 1.44 (95% CI, 1.10 – 1.87; P = .0068), and 1.54 (95% CI, 1.16 – 2.04;P = .0025), respectively, in a model adjusted for age, race, and sex. Associations were reduced after adjustment for stroke risk factors.

With distress modeled categorically and adjusting for age, race, and sex, participants in the highest quartile had nearly a 3 times (HR, 2.97; 95% CI, 1.81 – 4.88; P < .0001) greater risk of dying from stroke relative to those with the lowest distress scores. Those in the third quartile had nearly 2 times the risk (HR, 1.98; 95% CI, 1.19 – 3.30; P = .0091).

Analyses of stroke subtypes revealed that distress was significantly related to incident hemorrhagic strokes, but not to ischemic strokes after adjustment for covariates.

Behavioral Factors

Psychological and behavioral factors may play a role in raising stroke risk. Very distressed people may be less likely or less able to comply with treatment recommendations or to maintain a healthy lifestyle.

“Our most distressed participants were less physically active, and had a higher prevalence of cardiovascular disease and diabetes mellitus, suggesting potentially greater disease burden in this group, which could make lifestyle management more challenging,” the authors write. However, in this study, controlling for these factors had little effect on the relationship between distress and either stroke mortality or hemorrhagic strokes.

The pathways by which distress increases stroke risk are not fully understood, said the authors. Possible mechanisms may involve hypothalamic-pituitary-adrenal dysregulation related to stress that may increase circulating catecholamines, endothelial dysfunction, and platelet activation, culminating in a hypercoaguable state.

Neuroendocrine and inflammatory effects of chronic stress and negative emotional states may also contribute to the increased risk. However, the authors pointed out that these pathways are probably more important for ischemic than hemorrhagic stroke and that the current study found much stronger findings for hemorrhagic stroke.

The study lacked data on inflammatory and neuroendocrine biomarkers that might have shed more light on pathways that may link psychosocial distress to stroke risk. Another limitation was that CHAP doesn’t include imaging data that might provide important information about the types of strokes experienced by study participants. Also, the study assessed psychosocial distress at just one point in time, so it couldn’t determine whether distress levels changed or whether such changes influenced stroke risk.

Dr. Everson-Rose is supported in part by a grant from the National Institute on Minority Health and Health Disparities (NIMHD).

Stroke. Published online December 13, 2012.

Retrieved from: http://www.medscape.com/viewarticle/776137?src=smo_neuro

Managing Holiday Anxieties | Anxiety and Depression Association of America, ADAA

In Anxiety, Mood Disorders on Friday, 23 November 2012 at 11:03

Managing Holiday Anxieties | Anxiety and Depression Association of America, ADAA.

the state of anxiety in the united states

In ADHD, Anxiety, Medication, Psychiatry, Psychopharmacology on Wednesday, 3 October 2012 at 05:51

Some Facts about Anxiety in the United States:

Anxiety disorders are the most common mental illness in the U.S., affecting 40 million adults in the United States age 18 and older (18% of U.S. population).

Anxiety disorders are highly treatable, yet only about one-third of those suffering receive treatment.

Anxiety disorders cost the U.S. more than $42 billion a year, almost one-third of the country’s $148 billion total mental health bill, according to “The Economic Burden of Anxiety Disorders,” a study commissioned by ADAA (The Journal of Clinical Psychiatry,60(7), July 1999).

More than $22.84 billion of those costs are associated with the repeated use of health care services; people with anxietydisorders seek relief for symptoms that mimic physical illnesses.

People with an anxiety disorder are three to five times more likely to go to the doctor and six times more likely to be hospitalized for psychiatric disorders than those who do not suffer from anxiety disorders.

Anxiety disorders develop from a complex set of risk factors, including genetics, brain chemistry, personality, and life events.

 

Facts: Anxiety and Stress-Related Disorders

Generalized Anxiety Disorder (GAD)

GAD affects 6.8 million adults, or 3.1% of the U.S. population.
Women are twice as likely to be affected as men.

Obsessive-Compulsive Disorder (OCD)
2.2 million, 1.0%
Equally common among men and women.
The median age of onset is 19, with 25 percent of cases occurring by age 14. One-third of affected adults first experienced symptoms in childhood.

  • Hoarding is the compulsive purchasing, acquiring, searching, and saving of items that have little or no value.

Panic Disorder

6 million, 2.7%
Women are twice as likely to be affected as men.
Very high comorbidity rate with major depression.

Posttraumatic Stress Disorder (PTSD)
7.7 million, 3.5%
Women are more likely to be affected than men.
Rape is the most likely trigger of PTSD: 65% of men and 45.9% of women who are raped will develop the disorder.
Childhood sexual abuse is a strong predictor of lifetime likelihood for developing PTSD.

Social Anxiety Disorder
15 million, 6.8%
Equally common among men and women, typically beginning around age 13.
According to a 2007 ADAA survey, 36% of people with social anxiety disorder report experiencing symptoms for 10 or more years before seeking help.

Specific Phobias
19 million, 8.7%
Women are twice as likely to be affected as men.

Related Illnesses 

Many people with an anxiety disorder also have a co-occurring disorder or physical illness, which can make their symptoms worse and recovery more difficult. It’s essential to be treated for both disorders.

Children 

Anxiety disorders affect one in eight children. Research shows that untreated children with anxiety disorders are at higher risk to perform poorly in school, miss out on important social experiences, and engage in substance abuse.

Anxiety disorders also often co-occur with other disorders such as depression, eating disorders, and attention-deficit/hyperactivity disorder (ADHD).

Older Adults

Anxiety is as common among older adults as among the young. Generalized anxiety disorder (GAD) is the most common anxiety disorder among older adults, though anxiety disorders in this population are frequently associated with traumatic events such as a fall or acute illness. Read the best way to treat anxiety disorders in older adults.

Treatment Options

Anxiety disorders are treatable, and the vast majority of people with an anxiety disorder can be helped with professional care. Several standard approaches have proved effective:

Retrieved from: http://www.adaa.org/about-adaa/press-room/facts-statistics

 

The United States of Anxiety

By Ben Michaelis, Ph.D.

America is in an acute state of anxiety. For those of you who were concerned during the debt ceiling discussions, have been fearful during the stock market gyrations and are now panicking about your job, family and future, take a moment, take a deep breath and imagine that there is a better way. Because there is.

As human beings, our minds are prewired to react more strongly to negative information than positive information. This makes sense from an evolutionary psychology perspective: Negative information may mean threats to our survival, such as predators who may try to eat us. This is the reason that when a stranger gives you a nasty look it stays on your mind longer than when someone flashes a smile at you. This natural bias towards focusing on the negative becomes even more pronounced during times of uncertainty. When we don’t know where to turn, anything that seems potentially dangerous grabs our attention and activates our primitive survival instincts.

The fight or flight system is quite useful when you are facing a specific physical threat, but it is not helpful when you are facing general uncertainty, which is really what this is about. In fact, our survival instincts actually steer us in the wrong direction and can quickly make the situation worse. What is needed during periods of uncertainty is not this primitive instinct toward biological survival, which drove investors to “sell, sell sell!” on Monday, but rather the capacity to use our higher brain centers to imagine a different future.

As a clinical psychologist, I don’t treat nations, I treat people. In my work, I often see patients who experience intense, runaway anxiety (not unlike what happened on Monday) at just the time of a triumph or when things are about to turn for the better. Giving into the fear of the moment is both psychologically unpleasant and socially contagious. When other people see, or sense, that you are afraid, they focus on their instinctive reaction to seeing your fear and begin to experience terror themselves. Societal fear can quickly create an environment where your fears can come true simply by people behaving as though they are true. Regardless of the headlines suggesting the end is nigh, try taking a beat and doing something different: Imagine that all is not lost. Consider the ways that the future might actually be better than the present or the past.

When I am with a patient who is in the grip of such a panic, I suggest following these three steps in order to shift from fear to faith:

  1. Recognize: If you can recognize that you are in a state of panic, you are, frankly, more than halfway to stopping it. If you are not sure if you are in a state of panic, ask yourself this question: “Can I choose to stop these unpleasant, spiraling thoughts if I want to?” If the answer to the question is, “Yes,” then go ahead and do it. If the answer is “No,” then you have just realized that you are panicking.
  2. Refocus: Focus your energy on your five senses. Ask yourself: “What am I smelling?” “What am I seeing?” “What am I hearing?” “What are the tastes in my mouth?” and “How is my body feeling?” If you intentionally bring your focus away from the scenarios of Armageddon (not the Bruce Willis version) that you are cooking up and unto your present circumstances, you will break the chain of runaway thinking, because you can’t do both simultaneously. Even if you only get a brief respite any break, no matter how small, is enough to change the direction of your anxiety and help you take an active approach to problem solving.
  3. Re-imagine: Take your doomsday scenario and re-write it so that you are not stuck with the same old script. Write a Hollywood ending if you like. If you are scared that you will lose all of your money in the stock market, imagine the opposite. Picture the market changing direction, and that you will have more than you will ever need. If you have been out of work and are afraid that you will never get another job, imagine that you will be inundated with job offers. I am not suggesting that by simply imagining these things that they will happen, only that by doing so you can stop the spiral of anxiety and start thinking and planning for your next steps. That shift can make all of the difference between fueling the contagion of panic and returning to a more balanced state where you can actually effect real change in your life.

Your imagination is your greatest cognitive gift. It is also our greatest national asset. The ability to imagine a different and better future is the first step toward creating one. By recognizing, refocusing and re-imagining your circumstances you will feel better in the moment and shift from fear to faith. Using your mind’s eye to envision a positive outcome can help calm you down and make better momentary decisions. Plus, you might just inspire others to do the same.

Retrieved from: http://www.huffingtonpost.com/ben-michaelis-phd/americans-anxiety-stress_b_925420.html

 

are we over-medicating?

In ADHD, Anxiety, Brain imaging, Brain studies, Medication, Psychiatry, Psychopharmacology on Wednesday, 3 October 2012 at 05:39

this is one author’s opinion on anxiety and “the little blue pill.”  while anxiety is a VERY REAL and often debilitating condition for some, many wonder if anxiety medications (such as xanax and valium) are too readily prescribed and taken.  in my work as a school psychologist, i am asked constantly if i think adhd is over-diagnosed and children are over-medicated.  my answer is based in my belief that most psychological conditions are brain-based (this is becoming especially evident in light of new ways to examine the brain, i.e. genomic medicine, advanced brain imaging, etc.).  not treating those who have a REAL diagnosis has deleterious effects, but do i think that there are many physicians who will prescribe medications without possibly doing a full evaluation?  yes, i do.  but, i also think there are some VERY savvy parents who know what to say to get their kids medication that they *think* will give them an advantage over others.  while stimulants have a paradoxical effect on those with adhd (meaning they are stimulants but do not act as a stimulant behaviorally, i.e. not hyping kids up, but stimulating parts of the brain that are responsible for attending, focus, etc., thus appearing to calm them down), they also act as true stimulants for those that do not have a valid adhd diagnosis.  there are many stories of all-night study sessions in college and kids who use stimulants to stay awake and keep studying (i have even heard about kids who purchase stimulants just as they would marijuana or other drugs and crush it up and snort it for a cocaine-like effect).  the effect of a stimulant on someone without adhd is much like that of someone on cocaine.  they are ‘stimulated.’  so, while i believe the author has some valid points related to medication, i also believe that people who TRULY have a diagnosis of anxiety, adhd, depression, etc., do more harm than good when they do not take medication.  that is my personal opinion based on the many studies of those with treated issues versus those who do not seek treatment or were not treated until adulthood.  the differences in neuroanatomy and structural changes in the brain show that medication does work IF properly prescribed.  my personal opinion is if you think you are suffering from a brain-based disorder (adhd, anxiety, etc.), do yourself a favor and go to a PSYCHIATRIST.  while pediatricians and general practitioners are good at what they do and are knowledgeable about so many things, you wouldn’t go to an ophthalmologist for a broken leg, so why would you go to a pediatrician for a psychiatric issue?  psychiatrists’ entire business is of the mind and it is their job to keep up with the latest research and medications.  why go to anyone BUT a specialist?  once again, this is nothing more than my PERSONAL opinion.  

Valium’s Contribution to the New Normal

OPINION

By Robin Marantz Henig

IT wasn’t funny, really, but everybody laughed at the scene in the 1979 film “Starting Over” when Burt Reynolds’s character had a panic attack in the furniture department of Bloomingdale’s (something to do with terror at the prospect of buying a couch). “Does anyone have a Valium?” his brother called out as Burt hyperventilated. The punch line: Every woman in the store reached into her purse and pulled out a little vial of pills.

Nor was it surprising that all those Bloomie’s shoppers could be so helpful, since by that time Valium, which had been introduced in 1963, was the best-selling prescription drug in America, with billions of blue or yellow or white pills, each stamped with a trademark V, sold every year.

Valium was, significantly, one of the first psychoactive drugs to be used on a large scale on people who were basically fine. It has since been surpassed by other drugs, like the popular tranquilizer Xanax. But with the pharmaceutical giant Roche announcing that it will soon close the Nutley, N.J., plant where Valium and its predecessor, Librium, were developed, it’s a good time to remember how revolutionary these “minor tranquilizers” were half a century ago. These were the drugs that gave us a new way to slay our inner demons, medicating our way to a happier life.

How did Roche convince physicians that it was O.K. to offer their patients a bottled form of serenity? How did the physicians persuade their patients? And how did the company’s success in this venture shape our collective attitudes toward normal versus abnormal, stoic versus foolhardy, and the various ways available to cope with the ups and downs of daily life?

Marketing, essentially — which was first put into action with Librium, one of those evocative drug names that pharmaceutical companies invent. Librium was introduced in 1960 and promptly outsold its predecessors, the barbiturates, because it had fewer side effects. (Barbiturates were serious downers, making people sleepy and zombielike, and they were habit-forming; Marilyn Monroe died from an overdose.)

“A Whole New World … of Anxiety” read one of the early Roche ads for Librium, featuring a young woman with a pageboy hairdo holding an armload of books, wearing a short stadium coat and heading off to college. The copy made it sound as though every step in this “whole new world” called out for a tranquilizer. “The new college student may be afflicted by a sense of lost identity in a strange environment … Her newly stimulated intellectual curiosity may make her more sensitive to and apprehensive about unstable national and world conditions.”

The ad lists other sources of “anxiety” in a college student’s life — new friends, new influences, stiff competition for grades and tests of her moral fiber — that could just as easily be seen as growing pains, or as a healthy response to the turbulent world of the 1960s, when this ad appeared in The Journal of the American College Health Association. But Roche wanted doctors to believe that they were problems, not adventures, and that they warranted a prescription for Librium.

The next step was to develop something better — stronger, faster acting, less toxic. The Roche chemist who had originally stumbled upon Librium, Leo Sternbach, went back to the lab and tweaked the compound. Then he tested the drug on humans — in this case, the mothers-in-law of a few Roche executives. The executives thought that the new drug, Valium, rendered their mothers-in-law significantly less annoying.

In retrospect, Librium turned out to be a great first act, teaching Roche how to pitch a psychoactive drug to doctors of healthy patients who just needed a little something to unjangle their nerves. By the time Valium arrived, Roche was poised to dominate the field. In 1974, Americans filled nearly 60 million prescriptions for Valium.

Taking a pill to feel normal, even a pill sanctioned by the medical profession, led to a strange situation: it made people wonder what “normal” really was. What does it mean when people feel more like themselves with the drug than without it? Does the notion of “feeling like themselves” lose its meaning if they need a drug to get them there?

At the same time that Valium became famous for being in everyone’s medicine chest (or in every department store shopper’s purse), it also became famous for ruining lives. Elizabeth Taylor said she was addicted to Valium plus whiskey, Jack Daniel’s in particular. Tammy Faye Bakker said she was addicted to Valium plus nasal spray. Elvis Presley’s personal poison was Valium mixed with an assortment of other prescriptions. And Karen Ann Quinlan, the young woman languishing in a chronic vegetative state while her parents fought all the way to the New Jersey Supreme Court for the right to remove her from life support, originally lapsed into a coma in 1975 from a combination of Valium and gin.

Nearly 50 years after Valium was introduced and aggressively marketed, we’ve learned its lessons well. My generation of aging baby boomers does its brain styling, by and large, with antidepressantsProzac, Wellbutrin, CelexaPaxilZoloft. And for my daughters’ generation, the millennials, the pills of choice tend to be Ritalin and Adderall, for mental focus.

But when Americans are feeling out of sorts, we are still more likely to turn to anti-anxiety drugs than to any other kind. The leading successor to Valium, Xanax, outsells every other psychiatric drug on the market (48.7 million prescriptions last year). And even Valium is still out there, the classic little-black-dress of tranquilizers. In 2011, 14.7 million prescriptions were written for the drug that first made its cultural mark as a Rolling Stones song (“Mother’s Little Helper”) back in 1966.

As Roche closes its New Jersey headquarters, it plans to open a smaller research facility in Manhattan in late 2013, part of a wave that city officials hope will turn New York into a biotech mecca. The company’s transition reminds us of a phenomenon that’s become so common we no longer even think of it as weird: the oxymoronic attainment, through using drugs to make you feel more like yourself, of an artificially induced normal.

Robin Marantz Henig is a contributing writer for The New York Times Magazine and the co-author, with her daughter Samantha Henig, of the forthcoming “Twentysomething: Why Do Young Adults Seem Stuck?”

Retrieved from: http://www.nytimes.com/2012/09/30/sunday-review/valium-and-the-new-normal.html?ref=opinion&_r=0

Tailoring Antidepressant Treatment

In ADHD, ADHD Adult, ADHD child/adolescent, Anxiety, Medication, Psychiatry, Psychopharmacology on Monday, 24 September 2012 at 07:13

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

References:

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Retrieved from:

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

References:

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000.
  2. Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide. Cambridge, Mass: Cambridge University Press; 2005.
  3. FDA Package Insert. Pristiq. Pfizer Inc. 2011.
  4. FDA Package Insert. Viibryd. Forest Laboratories, Inc. 2011.
  5. Davidson J, Baldwin D, Stein DJet al.Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry. 2006;63:1158-1165. Abstract
  6. Bandelow B, Zohar J, Hollander E, et al. World federation of societies of biological psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders — first revision. World J Biol Psychiatry. 2008;9:248-312. Abstract
  7. Benedek DM, Friedman MJ, Zatzick D, et al. Guideline watch (March 2009): practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder.
  8. Phelps NJ, Cates ME, The role of venlafaxine in the treatment of obsessive-compulsive disorder. Ann Pharmacother. 2005;39:136-140. Abstract
  9. Gartlehner G, Hansen RA, Reichenpfader U, et al. Drug class review: second-generation antidepressants: final update 5 report [internet].Portland, Ore: Oregon Health & Science University; March 2011.
  10. Effexor Prescribing Information. http://labeling.pfizer.com/showlabeling.aspx?id=100
  11. FDA Package Insert. Cymbalta. Lilly USA LLC. 2004/2011.
  12. FDA Package Insert. Silenor. Somaxon Pharmaceuticals Inc. 1969.
  13. Hsu, ES. Acute and chronic pain management in fibromyalgia: updates on pharmacotherapy. Am J Ther. 2011;18:487-509. Abstract
  14. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs. 2008;68:2611-2632. Abstract
  15. Prince JB, Wilens TE, Biederman J, et al. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2000;10:193-204. Abstract
  16. Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS Spectr. 2003;8:253-258. Abstract
  17. Wilens TE, Prince JB, Spencer T, et al, An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder. Biol Psychiatry. 2003;54:9-16. Abstract
  18. Olvera RL, Pliszka SR, Luh J, et al. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1996;6:241-250. Abstract
  19. Sadock BJ, Sadock VA, et al. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Tenth ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2007:977-1126.
  20. Prochazka AV, Kick S, Steinbrunn C, et al. A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation. Arch Intern Med. 2004;164:2229-2233. Abstract
  21. FDA Package Insert. Wellbutrin XL. GlaxoSmithKline. 2008.
  22. McIntyre RS, Mancini DA, McCann S, et al, Topiramate versus bupropion SR when added to mood stabilizer therapy fpr the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4:207-213. Abstract
  23. Coleiro B, Marshall SE, Denton CP, et al. Treatment of raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology. 2001;40:1038-1043. Abstract
  24. Stearns V, Beebe KL, Iyengar M, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827-2834. Abstract
  25. Evans ML, Pritts E, Vittinghoff E, et al. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105:161-166. Abstract
  26. Muller D, Roehr CC, Eggert P. Comparative tolerability of drug treatment for nocturnal enuresis in children. Drug Saf. 2004;27:717-727. Abstract
  27. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge, Mass: Cambridge University Press; 2008:511-666.
  28. Spina E, Scordo MG. clinically significant drug interactions with antidepressants in the elderly. Drugs Aging. 2002;19:299-320. Abstract
  29. FDA Packet Insert. Celexa. Forest Laboratories, Inc. 2010/2011.
  30. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30:1206-1227. Abstract
  31. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758. Abstract
  32. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991. Abstract
  33. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology (Berl). 1986;90:131-138. Abstract
  34. Danish University Antidepressant Group.Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord. 1990;18:289-299. Abstract
  35. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry. 1994;151:1735-1739. Abstract
  36. Beasley CM Jr, Holman SL, Potvin JH. Fluoxetine compared with imipramine in the treatment of inpatient depression. A multicenter trial. Ann Clin Psychiatry. 1993;5:199-207. Abstract
  37. Bailey J. Acute psychosis after bupropion treatment in a healthy 28-year-old woman. J Am Board Fam Med. 2008;21:244.
  38. Rush AJ, Trivedi MH, Wisnewlski Sr, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163:1905-1917. Abstract
  39. Zajecka JM, Goldstein C. Combining medication to achieve remission. In: Schwartz T, Petersen T, eds. Depression: Treatment Strategies and Management. 2nd ed. New York: Informa; 2009.
  40. Park K, ed. Controlled Drug Delivery: Challenges and Strategies. Washington, DC: American Chemical Society; 1997.
  41. Orange book annual preface, statistical criteria for bioequivalence. In: Approved Drug Products with Therapeutic Equivalence Evaluations. 29th ed. US Food and Drug Administration Center for Drug Evaluation and Research; 2009-06-18, update 3-01-11. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm

Retrieved from: http://www.medscape.org/viewarticle/755180

The state of sleep in the U.S.

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Anxiety, Fitness/Health, Medication, Well-being on Tuesday, 18 September 2012 at 05:04

stress, anxiety, and depression are but three related etiologies for insomnia.  people with ADHD also suffer from insomnia, either as a side-effect of psychostimulants or because of the ADHD itself.  insomnia can have significant effects on quality of life, work/school life, and health.  statistics show that insomnia is a growing problem in the U.S. today and sleep aids are being prescribed at an increasing rate.  the following are some statistics related to insomnia as well as a case-study/research article on insomnia. 

to be followed by an article about hypnotic use and associated risk-factors.

***

General Insomnia Statistics

  • People today sleep 20% less than they did 100 years ago.
  • More than 30% of the population suffers from insomnia.
  • One in three people suffer from some form of insomnia during their lifetime.
  • More than half of Americans lose sleep due to stress and/or anxiety.
  • Between 40% and 60% of people over the age of 60 suffer from insomnia.
  • Women are up to twice as likely to suffer from insomnia than men.
  • Approximately 35% of insomniacs have a family history of insomnia.
  • 90% of people who suffer from depression also experience insomnia.
  • Approximately 10 million people in the U.S. use prescription sleep aids.
  • People who suffer from sleep deprivation are 27% more likely to become overweight or obese. There is also a link between weight gain and sleep apnea.
  • A National Sleep Foundation Poll shows that 60% of people have driven while feeling sleepy (and 37% admit to having fallen asleep at the wheel) in the past year.
  • A recent Consumer Reports survey showed the top reason couples gave for avoiding sex was “too tired or need sleep.”

Financial Implications of Insomnia

Insomnia statistics aren’t confined to the relationship between insomnia and health. This sleep disorder costs government and industry billions of dollars a year.

  • The Institute of Medicine estimates that hundreds of billions of dollars are spent annually on medical costs that are directly related to sleep disorders.
  • The National Highway Traffic Safety Administration statistics show that 100,000 vehicle accidents occur annually drowsy driving. An estimated 1,500 die each year in these collisions.
  • Employers spend approximately $3,200 more in health care costs on employees with sleep problems than for those who sleep well.
  • According to the US Surgeon General, insomnia costs the U.S. Government more than $15 billion per year in health care costs.
  • Statistics also show that US industry loses about $150 billion each year because of sleep deprived workers. This takes into account absenteeism and lost productivity.

These sobering insomnia statistics underscore the importance of enhancing sleep disorder awareness and why individuals need to seek immediate treatment for the health and the well-being of others.

Sources: National Sleep Foundation, Better Sleep Council, Gallup Polls, Institute of Medicine, National Highway Traffic Safety Administration, US Surgeon General’s Office

http://www.better-sleep-better-life.com/insomnia-statistics.html

Manifestations and Management of Chronic Insomnia: NIH State-of-the-Science Conference Findings and Implications

Authors: William T. Riley, PhD; Carl E. Hunt, MD

http://www.medscape.org/viewarticle/517618

Introduction

The Problem of the Inadequate Identification and Treatment of Chronic Insomnia

Despite considerable advances in the understanding of and treatments for chronic insomnia, this condition remains inadequately identified and treated. Approximately one third of US adults report difficulty sleeping, and 10% to 15% have the clinical disorder of insomnia.[1] Among primary care patients, approximately half have sleep difficulties, but these difficulties often are undetected by health professionals.[2,3] Even if detected and appropriately diagnosed, these patients are more likely to receive treatments of questionable safety and efficacy rather than treatments with substantial, evidence-based support for safety and efficacy.

The inadequate identification and treatment of chronic insomnia has serious medical and public health implications. Chronic insomnia results in impaired occupational performance and diminished quality of life.[4,5] Insomnia is associated with higher healthcare usage and costs, including a 2-fold increase in hospitalizations and physician visits.[6] Insomnia is also a risk factor for a number of other disorders, particularly psychiatric disorders, such as depression, and an important sign or symptom for a range of medical and other psychiatric disorders.[7]

In a recent review, Benca[8] identified the following 5 barriers to the recognition, diagnosis, and treatment of insomnia in primary care settings:

  • Inadequate knowledge base: In the 1990s, about one third of medical schools had no formal sleep medicine training. A majority of practitioners rate their knowledge of sleep medicine as only “fair.”
  • Office visit time constraints: Unless sleep difficulties are the presenting complaint, visit time may be inadequate for sleep difficulties to be addressed.
  • Lack of discussion about sleep: Less than half of patients with insomnia have discussed this problem with their physicians, and most of these discussions were patient-initiated.
  • Misperceptions regarding treatment: Health professionals may have greater concerns than warranted about the safety and efficacy of pharmacologic treatments, and they may not be aware of or have access to effective nonpharmacologic approaches.
  • Lack of evidence for functional outcomes: Although treatments for insomnia reduce symptoms in the short term, there is inadequate evidence for long-term efficacy, improvements in daytime functioning, or the impact on comorbid disorders.

Addressing these barriers could lead to improved recognition and treatment of chronic insomnia and may substantially reduce the personal and public health burden of this disorder.

The Importance of Appropriate Recognition and Treatment of Chronic Insomnia: NIH State-of-the-Science Conference Statement

The purpose of this Clinical Update is to emphasize the importance of appropriate recognition of and treatment for chronic insomnia based on the recently published statement from the National Institutes of Health (NIH) State-of-the-Science Conference on the Manifestations and Management of Chronic Insomnia in Adults.[9] An independent panel of health professionals convened in June 2005 to evaluate the evidence from (1) systematic literature reviews prepared by the Agency for Health Research and Quality, (2) presentations by insomnia researchers over a 2-day public session, (3) questions and comments by conference attendees during the public sessions, and (4) closed deliberations by the panel. This process resulted in a State-of-the-Science (SOS) Conference Statement on chronic insomnia, including implications for clinical and research efforts.

The SOS Conference proceedings and statement were organized around the following 5 questions, which serve as the outline for this Clinical Update:

  • How is chronic insomnia defined, diagnosed, and classified, and what is known about its etiology?
  • What are the prevalence, natural history, incidence, and risk factors for chronic insomnia?
  • What are the consequences, morbidities, comorbidities, and public health burden associated with chronic insomnia?
  • What treatments are used for the management of chronic insomnia, and what is the evidence regarding their safety, efficacy, and effectiveness?
  • What are important future directions for insomnia-related research?

The SOS Conference focused on adults with chronic insomnia, not acute or episodic manifestations, which typically resolve in a few weeks, often without intervention. Although secondary or comorbid insomnia (insomnia associated with other conditions) was considered with respect to diagnosis and classification, the conference focused on the treatment of primary insomnia, not on any existing comorbid conditions. This Clinical Update, therefore, follows the scope of the SOS Conference and focuses on chronic primary insomnia in adults. Information in the SOS Conference Statement is augmented by the research literature, including a number of excellent, recent reviews on the clinical management of insomnia.[8,10-14]

How Is Chronic Insomnia Defined, Diagnosed, and Classified, and What Is Known About Its Etiology?

Case Study: Part 1

A 56-year-old woman presents for routine monitoring of postmenopausal symptoms and bone density, following a 2-year course of hormone replacement therapy that was initiated 5 years ago when she began experiencing hot flashes and depressive symptoms. During the visit, she is asked about her sleep and reveals that she has difficulty falling asleep most nights and sometimes awakens in the middle of the night, and is unable to go back to sleep. She notes frustration at her inability to get a good night’s sleep, particularly because she often feels tired and has difficulty concentrating at work. She reports that her insomnia began about the time of her menopausal symptoms, but has continued even though her other menopausal symptoms have resolved.

What steps should be taken to diagnose her condition?

Detecting Sleep Difficulties

The patient in the case above has a distinct advantage over many patients who suffer with insomnia because her healthcare professional specifically asked about her sleep. As early as Hippocrates, sleep has been an important indicator of patient health. “Disease exists, if either sleep or watchfulness be excessive”: Hippocrates, Aphorism LXXI.[12] In a recent study of adult primary care patients with insomnia, only about half reported discussing insomnia with their physicians.[15] Other studies have found that only 10% to 30% of those with insomnia discussed this problem with their physicians,[16] and most healthcare providers fail to ask about sleep.[2] Asking a simple question, such as “How have you been sleeping?” can lead to the detection of insomnia and a range of other sleep-related conditions.[17]

Definitions and Diagnostic Criteria for Chronic Insomnia. Insomnia is a sleep disturbance that most often manifests as difficulty initiating sleep, but also manifests as difficulty maintaining sleep or experiencing early-morning awakenings.

How much sleep disruption is sufficient for the diagnosis of insomnia? Normal sleep needs vary greatly from individual to individual. Moreover, the degree of sleep disturbance in those with insomnia can be quite variable from night to night, including nights without any sleep disturbance. Although quantitative indices for sleep-onset latency (≥ 30 minutes) and for sleep efficiency (percentage of total time asleep over total time in bed ≤ 85%) have been used for research purposes,[18] these indices do not correlate well with the patient’s experience of insomnia.[19] Therefore, the subjective experience of inadequate sleep is frequently more important than quantitative sleep indices in diagnosing insomnia.

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defines primary insomnia as a difficulty initiating or maintaining sleep or experiencing nonrestorative sleep that results in clinically significant distress or impairment in functioning.[20] Based on these criteria, someone who does not appear to have objective manifestations of sleep disturbance but whose sleep is sufficiently inadequate or nonrestorative to produce distress or dysfunction would meet the criteria for insomnia. In contrast, someone who gets only a few hours of sleep each night but feels rested and without associated distress or dysfunction does not meet the criteria for insomnia. Therefore, subjective impressions of nonrestorative sleep with associated distress or dysfunction are important symptoms of insomnia.

These complaints of disturbed sleep also must occur in the context of adequate opportunity and circumstances for sleep. Although disruption of sleep from environmental perturbations may place someone at risk for insomnia, sleep disruption is not classified as insomnia unless there is adequate opportunity to sleep. Resident physicians on call or mothers of newborns commonly experience sleep disturbances, nonrestorative sleep, and daytime distress or impairment from inadequate sleep, but these problems are not diagnosed as insomnia because they are the result of having an inadequate opportunity to sleep.

Many people experience insomnia on occasion, but most of these “acute” or “episodic” forms of insomnia are transient and typically resolve without treatment. The duration required for insomnia to be “chronic” has varied from as little as 1 month to as long as 6 months. Based primarily on recent Research and Diagnostic Criteria (RDC) for insomnia,[21] the SOS Conference Statement concluded that insomnia lasting 1 month or more is clinically important and indicates the need for professional attention.

The SOS Conference Statement concluded that insomnia lasting 1 month or more is clinically important and indicates the need for professional attention.

RDC for insomnia. The Academy of Sleep Medicine recently developed RDC for insomnia[21] in an effort to merge different nosologies and improve the diagnostic reliability of insomnia. The RDC criteria also provide 3 subclassifications of primary insomnia: Psychophysiologic Insomnia, Paradoxical Insomnia (Sleep State Misperception), and Idiopathic Insomnia, which may facilitate research on potential etiologies of this disorder. These diagnostic criteria will be included in the second edition of the International Classification of Sleep Disorders (ICSD-2) and will likely be adopted in the next International Classification of Diseases (ICD) version. The RDC diagnostic scheme first delineates the criteria for an insomnia disorder and then specifies the exclusion criteria for primary insomnia. Compared with the DSM-IV criteria, the RDC insomnia criteria specify the requirement for adequate opportunity or circumstances for sleep and provide greater detail of the distress or functional impairment criteria. The RDC criteria for primary insomnia also clarify that the presence of a comorbid disorder does not exclude the diagnosis of primary insomnia unless the insomnia can be attributed exclusively to the comorbid disorder.

Comorbid insomnia. Primary insomnia is a diagnosis of exclusion. Numerous other conditions can contribute to the onset or maintenance of insomnia, including psychiatric disorders, substance abuse, other sleep disorders, or medical conditions/treatments. In the past, insomnia was considered “secondary” if it appeared due to another condition, but this was often difficult to determine clinically.[22] In addition, the relationship between insomnia and various comorbid disorders is complex and multidirectional. For example, insomnia may be a symptom of comorbid depression, but it may also be a separate and predisposing condition for depression.[23]

Given these complexities, the SOS Conference Panel recommended that “comorbid insomnia” replace the term “secondary insomnia.” The practical implication of this terminology for clinicians is that insomnia should not be relegated to secondary status whenever a comorbid disorder exists. The presence of comorbid disorders needs to be evaluated, and temporal relationships between the course of the comorbid disorder and the insomnia may shed light on possible etiologic relationships between them,[7] but it cannot be assumed that treating only the comorbid disorder will result in resolution of the insomnia as well.

The SOS Conference Panel recommended that “comorbid insomnia” replace the term “secondary insomnia.”

Clinical assessment of insomnia. The diagnosis of insomnia is based primarily on the patient’s history. Reports by family members, particularly the bed partner, can augment the assessment of sleep behavior and daytime functioning. Medical history and physical examination are also useful for determining the presence of possible comorbid syndromes.[7]

Sleep diaries are frequently used to document sleep-and-wake behaviors. In addition to providing data to support a diagnosis, these data are often used to devise treatment plans and to monitor treatment outcomes. Patients are typically instructed to complete the diary each morning after awaking and provide their best estimates of variables, such as time in bed, time of sleep onset, awakenings, and wake time. These data are only estimates by patients and tend to underestimate actual sleep time, but they are useful for assessing individual sleep patterns, possible factors associated with poor sleep, and changes in sleep over time. There are also a number of self-report instruments, a few of which have been adequately standardized and validated for monitoring outcomes.[24]

To provide more objective measures of sleep behavior, actigraphs or accelerometers have been used in research trials to infer sleep-and-wake behaviors from changes in the amount of movement. Although useful, actigraphs have not been fully validated and may underestimate sleep time if sleep is restless or fitful (eg, with comorbid restless legs syndrome). Actigraphs and other automated measures of sleep behavior have not typically been used in routine practice, but can provide more objective measures of sleep patterns, especially when the patient’s report is in question (eg, sleep-state misperception).[25]

Polysomnography remains the gold standard for measuring sleep-wake states; however, the American Academy of Sleep Medicine does not recommend polysomnography for the assessment of insomnia except when needed to rule out a comorbid disorder, such as sleep apnea.[26] In addition to expense, polysomnography is unlikely to provide an accurate representation of an insomnia patient’s sleep difficulties given the night-to-night variability of sleep behavior and influence of the sleep environment on insomnia symptoms.

The American Academy of Sleep Medicine does not recommend polysomnography for the assessment of insomnia except when needed to rule out a comorbid disorder, such as sleep apnea.

Etiology of insomnia. Although there is growing consensus about the appropriate diagnostic criteria and procedures for insomnia, the possible etiologic factors for insomnia remain poorly understood. Spielman’s 3 Ps — predisposing, precipitating, and perpetuating factors — is a useful model for organizing various etiologic factors.[27]

Very little is known about possible predisposing factors for insomnia. Other than some limited research suggesting familial aggregation,[28,29] there are no data on genetic predisposition for insomnia. There is considerable research on the neurobiology of sleep-wake states, including the inhibitory feedback loop involving the GABA and galanin neurons in the ventrolateral preoptic nucleus of the hypothalamus and the orexin or hypocretin neurons in the posterior hypothalamus, which serve as a “flip-flop” switch of major cortical arousal systems.[30,31] It remains unclear, however, how these systems are dysfunctional in insomnia. Deficiencies in endogenous melatonin or benzodiazepine receptors and hyperactivity of corticotropin-releasing factor neurons are possible etiologic factors, but further research is needed to better understand these potential etiologies for insomnia.[32]

The possible etiologic factors for insomnia remain poorly understood, and little is known about possible predisposing factors for insomnia.

Hyperarousal appears to be an important mechanism for insomnia. Research has shown increased brain glucose metabolism when awake or asleep, increased beta and decreased theta and delta during sleep, and increased adrenocorticotropic hormone activity.[33,34] Results from recent functional imaging studies provide additional support for the central nervous system hyperarousal hypothesis.[35]

Potential precipitating factors for insomnia are numerous and include many of the possible disorders that are comorbid with insomnia, such as psychiatric disturbance, sleep-wake schedule changes, medical conditions and their treatments, other sleep disorders, and substance use. Substances, including caffeine, theophylline and other stimulants, steroids, antihypertensives, and antidepressants, can also precipitate insomnia.[12] A recent study found that family, health, and work-school-related events were the most common precipitating factors for insomnia, and that even positive events can precipitate insomnia.[36]

There is general agreement that insomnia, regardless of how it is precipitated, is perpetuated by cognitive and behavioral mechanisms. Cognitive factors involved in perpetuating insomnia include misconceptions about normal sleep needs and stability, misattributions about the causes of sleep disturbance, and catastrophic worry about the daytime effects of inadequate sleep.[18,37] These dysfunctional beliefs often promote behaviors that are intended to improve sleep but are disruptive to sleep homeostasis and a consistent sleep-wake cycle (eg, taking naps and sleeping in late to “catch up” on sleep). These sleep-disruptive behaviors are further perpetuated by behavioral conditioning, which produces conditioned arousal to stimuli that would normally be associated with sleep.[38] It is important to recognize that these cognitive and behavioral perpetuating factors may be present in both comorbid and primary

What Are the Prevalence, Course, Incidence, and Risk Factors for Chronic Insomnia?

Prevalence of Chronic Insomnia

Estimates of the prevalence of insomnia vary depending on the definition used. Approximately one third of the general population complains of sleep disruption, and 9% to 15% of the population report associated daytime impairment consistent with the diagnosis of insomnia.[1] However, the proportion of those reporting sleep disturbance with daytime impairment who would meet the diagnostic criteria for insomnia is unclear. Among patients in primary care, the prevalence rates for insomnia are much higher, as high as 50%.[4] In a large survey of managed care participants, over one third experienced symptoms of insomnia, although less than 1% presented with an insomnia complaint.[39]

Incidence, Natural Course, and Duration of Chronic Insomnia

The SOS Conference Statement noted that there is very little known about the incidence, natural course, and duration of insomnia. Limited evidence suggests that insomnia is a chronic and persisting condition with low rates of spontaneous remission and possible recurrence after a period of remission, but these processes are poorly understood.

There is very little known about the incidence, natural course, and duration of insomnia.

Risk Factors for Chronic Insomnia

Given that most research on risk factors for insomnia is cross-sectional, not longitudinal, it is difficult to know whether potential risk factors are causal or correlational. The prevalence of insomnia is higher in divorced, separated, or widowed adults, and in those with lower education and income levels.[1] Insomnia is also more likely to occur in women, especially postmenopausal women.[1] There is an increased prevalence of insomnia in older adults, but it remains unclear to what extent this is independent of declining health and comorbid influences. Sleep patterns, however, do change with age. Older people experience more awakenings during the night, lower sleep efficiency, less sleep, more variable sleep, and lighter sleep than younger adults.[40]

Several psychiatric and medical disorders are associated with insomnia. As noted earlier, however, these relationships are complex and multidirectional. For example, research on the relationship between insomnia and depression indicates that it is more likely that insomnia is a risk factor for depression than that depression is a risk factor for insomnia. Insomnia appears to be predictive of a number of disorders, including depression, anxiety, alcohol abuse/dependence, drug abuse/dependence, and suicide.[41] Medical and sleep disorders that potentially disrupt sleep (eg, chronic pain conditions, such as arthritis, or sleep apnea) may be precipitants of or risk factors for insomnia. Substance abuse and the use of prescribed medications that can disturb sleep also can be risk factors for insomnia.

It is difficult to know whether potential risk factors are causal or correlational. Several psychiatric and medical disorders are associated with insomnia, but these associations are complex and multidirectional.

What Are the Consequences, Morbidities, Comorbidities, and Public Health Burden Associated With Chronic Insomnia?

Economic Costs of Insomnia

Insomnia is associated with high healthcare utilization. Walsh and Ustun[42] estimated annual direct total costs for insomnia at about $12 billion for healthcare services and $2 billion for sleep-promoting agents. People with insomnia have more medical problems and use more medications than those without insomnia, and they have double the number of office visits and hospitalizations as those without insomnia.[6,43]

The relative contribution of insomnia and comorbid conditions to these costs remains unclear. Indirect costs of insomnia are even less clear. In 1994, the economic costs of insomnia were estimated at $80 billion annually.[44,45] These indirect cost estimates are higher than those for other chronic conditions, such as rheumatoid arthritis,[46] but there are limited data available to reliably estimate the indirect costs of insomnia.

Effects of Insomnia on Functioning and Quality of Life

Sleep loss does result in impaired psychomotor and cognitive functioning, but these impairments are less pronounced for insomnia.[47] Despite the equivocal impact of insomnia on memory and cognitive functioning, insomnia is related to occupational role dysfunction, including increased absenteeism and decreased work performance.[4,43] These daytime impairments, however, may be more related to the chronic hyperarousal state[48] or to perceptions of sleep deprivation[49] than to actual sleep loss from insomnia.

In considering the consequences of insomnia, it is important to differentiate being sleepy from being tired or fatigued. Sleepiness involves recurrent episodes of being drowsy and involuntarily falling asleep in nonstimulating environments (ie, dozing off). Sleepiness is more often associated with other primary sleep disorders, such as narcolepsy, sleep apnea, and periodic limb movement disorder. In contrast, those with insomnia are often tired or fatigued but not sleepy.[48,50]

Insomnia is associated with substantial impairments in quality of life. Although insomnia is often considered more benign than most other chronic medical and psychiatric disorders, the impairments in quality of life in insomnia are comparable to those observed in diabetes, arthritis, and heart disease.[5] Quality of life also improves with treatment for insomnia, although not to the level of the normal population.[51]

Insomnia is associated with substantial impairments in quality of life that are comparable to the impairments observed in other chronic medical disorders.

Comorbidities and Morbidities

Approximately 40% of adults with insomnia also have a diagnosable psychiatric disorder.[16] In addition, approximately three quarters of people presenting to sleep clinics or general medical practices with insomnia have a comorbid psychiatric disorder.[52] Although there are a number of psychiatric disorders that are comorbid with insomnia (eg, generalized anxiety disorder, attention-deficit/hyperactivity disorder, and schizophrenia), depression has received the most attention. Insomnia was once considered only a symptom of depression or secondary to depression. Recent research, however, has consistently shown that insomnia is a predisposing factor for depression. Insomnia often occurs prior to the onset of depression,[53] and often precedes depression relapses.[54,55] Those with persistent insomnia are also much more likely to develop depression at a later time.[16,56] In addition to depression, insomnia is associated with an increased risk for suicide[57] and is a precipitant of manic episodes in those with bipolar disorder.[58]

Insomnia is common in other primary sleep disorders, such as sleep apnea (sleep-disordered breathing [SDB]), restless legs syndrome, and periodic limb movement disorder. In these cases, insomnia may be secondary or fully attributable to the underlying sleep disorder, but often is a comorbid disorder precipitated by the other primary sleep disorder but perpetuated by cognitive and conditioning factors.[59] SDB typically presents clinically with nonrestorative sleep complaints and disturbed sleep maintenance with normal sleep onset. Snoring and/or apnea episodes are often reported by the bed partners, but patients are typically unaware of their sleep-related symptoms. If positive indications of SDB are found during a clinical interview, then overnight sleep recording is typically performed to establish the diagnosis and determine its severity.[7,59] SDB may be exacerbated by benzodiazepines, so it is important to rule out this condition before proceeding with insomnia treatment.

A number of chronic medical conditions are associated with insomnia, including chronic pain syndromes, coronary heart disease, asthma, gastrointestinal disorders, vascular disorders, chronic fatigue, and endocrine and metabolic disorders.[7] In addition, substances, including caffeine, theophylline and other stimulants, steroids, antihypertensives, and antidepressants, can precipitate insomnia.[12]

Although many of the disorders comorbid with insomnia are associated with increased mortality rates, insomnia itself does not appear to be associated with higher mortality. In a recent longitudinal study, neither insomnia nor the use of hypnotics for insomnia increased the risk for mortality over a 6-year period.[60] Higher mortality has been associated with either too much or too little sleep, but not with insomnia disorder per se.[61,62]

Insomnia is frequently comorbid with psychiatric disorders, other primary sleep disorders, and chronic medical conditions.

What Treatments Are Used for the Management of Chronic Insomnia, and What Is the Evidence Regarding Their Safety, Efficacy, and Effectiveness?

Case Study: Part 2

The patient’s medical history reveals menopausal symptoms that were controlled on hormone replacement therapy and did not recur following discontinuation 3 years ago. Her insomnia symptoms, however, have continued and worsened in the past 5 years. The patient is otherwise healthy. She does not report pain at night, snoring or gasping for air during sleep, or restless legs. She does report awakening at least once a night to urinate, but indicates that she is sometimes unable to return to sleep after awakening.

The clinical interview reveals no other psychiatric disorder. She has no history of substance abuse or dependence, but does indicate that she has begun drinking a glass or 2 of wine at night to help her fall asleep. She describes primarily being unable to fall asleep, and says it takes her an hour or 2 to fall asleep most nights. She also describes awakening during the night, sometimes being unable to go back to sleep, and that these sleep-maintenance symptoms have worsened in the past 6 months. She reports hearing that older people can get by on less sleep, but that she feels tired and irritable after nights of inadequate sleep. She is beginning to believe that she is not functioning as well at work because of her sleep difficulties. She reports feeling particularly distressed in the evening as her bedtime approaches and worries whether she will get enough sleep to perform well the next day.

The patient is provided with general information about sleep and insomnia and reassured that her sleep difficulties can be managed. She is provided with a sleep diary and asked to record her sleep-wake patterns for 2 weeks and then to return with her husband to complete the evaluation.

At the second visit, her husband confirms that she does not snore loudly or excessively and does not appear to experience short bouts of not breathing while asleep. He reports that she does have difficulty going to sleep and will toss and turn for an hour or so before falling asleep. On 2-3 mornings each week, he wakes up and finds that she is not in bed but that she got up during the night and later fell asleep while watching television downstairs. On weekends, he usually lets her sleep in late. He reports that she is sometimes so tired after a bad night that she will come home from work and take a nap before dinner. Her sleep diary reveals an average sleep-onset latency of about 45 minutes each night, that she is awake for over an hour during the night on about half the nights, a mean total sleep time of 6 hours and 30 minutes per night, and a mean sleep efficiency of 82%.

Based on this assessment, what treatment approaches should be considered?

Cognitive Behavioral Therapy

Cognitive behavioral therapy for insomnia (CBTI) addresses the hyperarousal, cognitive, and conditioning factors that appear to perpetuate the disorder. CBTI typically consists of 5 major components:[38]

  • Sleep-hygiene strategies to promote a sleep environment and routine that promote sleep.
  • Relaxation therapy (progressive muscle relaxation, visual imagery, etc) to reduce physiologic arousal.
  • Cognitive restructuring to change dysfunctional attitudes about sleep (eg, attempting to will oneself to sleep or excessive worrying about the effects of not sleeping).
  • Stimulus control to reassociate the bed and bedroom with going to sleep instead of staying awake. These instructions include (1) going to bed only when sleepy, (2) establishing a standard wake-up time, (3) getting out of bed whenever awake in bed for 15 minutes or more, (4) avoiding doing sleep-incompatible behaviors (reading or watching television) while in bed, and (5) refraining from daytime napping.
  • Sleep restriction to condense time in bed to the average time typically asleep. For this component, the time to bed is set based on the average time asleep but not less than 5 hours, and then it is gradually increased as sleep efficiencies improve.

The American Academy of Sleep Medicine Task Force on nondrug alternatives for primary chronic insomnia[63] found that CBTI produced reliable and durable improvement in chronic insomnia. Nearly 80% of those treated with CBTI show measurable benefit, but the magnitude of the benefit varies. CBTI produces objective improvements as well as subjective improvements in sleep and appears to improve homeostatic sleep regulation.[64] Although most of the research on CBTI is with primary insomnia, CBTI has been shown to produce benefits for the comorbid condition as well as for the insomnia.[65]

Sleep hygiene is the component of CBTI that is most often provided by healthcare providers,[66] and patients tend to like and adhere to sleep-hygiene strategies.[67] Unfortunately, sleep hygiene appears to be the least effective CBTI component. Stimulus control and sleep restriction are the most effective CBTI components,[68] but patients have the most difficulty adhering to these components.[67]

When CBTI is compared with medications, sedative hypnotics appear to produce more rapid improvements, but the long-term safety and efficacy of sedative hypnotics are less well established than CBTI.[69,70] The efficacy of CBTI, particularly long-term, and the minimal apparent adverse effects of this treatment have resulted in it being considered a first-line treatment for primary insomnia.[70]

Challenges with CBTI. Although CBTI is clearly efficacious, accessibility to this treatment has been severely limited by a general lack of knowledge regarding efficacy, inadequate coverage of this treatment by insurance carriers, and a lack of professionals trained in CBTI, even at certified sleep disorder centers.[38] The treatment is generally well accepted by patients when they are provided this option,[71] and the treatment is relatively short. Although session dosage remains unclear, Edinger and Means[38] have suggested that 4 sessions at 2-week intervals may be optimal based on their review of this treatment approach.

To increase availability, researchers have experimented with alternative methods of CBTI treatment delivery. Treatment delivery in individual, group, or phone-based sessions appears to be equally helpful.[72] Although self-help interventions appear less effective than professional assistance, self-help versions of CBTI still provide modest benefit over controls.[73] Delivery of CBTI via the Internet and other technologies is a promising new approach area for potentially improving the accessibility of this efficacious treatment for insomnia.[74]

Although CBTI is not typically provided by primary care health professionals, recent efforts show this to be another potential strategy for providing this treatment to those with insomnia. Indeed, allied healthcare providers have been trained to deliver CBTI with some success.[75] Recently, Edinger and Sampson[76] devised a “primary care friendly” form of CBTI. This abbreviated form of CBTI involves two 25-minute sessions 2 weeks apart. Session 1 consists of reviewing sleep logs and providing sleep education, stimulus control, and sleep-restriction instructions, such as eliminating activities that are incompatible with sleep, avoiding daytime naps, and setting up a consistent sleep-wake schedule (including sleep restriction). Session 2 consists of reviewing progress, addressing adherence difficulties, and modifying sleep strategies accordingly. This abbreviated treatment was significantly better than sleep-hygiene instructions alone for most insomnia measures and resulted in reductions of insomnia symptoms to normal levels in over half of patients.[76]

Although CBTI is efficacious, accessibility to this treatment has been severely limited by a general lack of knowledge regarding efficacy, inadequate coverage of this treatment by insurance carriers, and a lack of professionals trained in CBTI, even at certified sleep disorder centers.

US Food and Drug Administration-Approved Medications

Benzodiazepine and nonbenzodiazepine hypnotics. Both benzodiazepine and nonbenzodiazepine hypnotics have been approved for the treatment of insomnia.

Benzodiazepine hypnotics. The benzodiazepine hypnotics approved by the US Food and Drug Administration (FDA) for the treatment of insomnia are estazolam, flurazepam, quazepam, temazepam, and triazolam. These medications have been found effective in a number of double-blind, placebo-controlled trials, but these trials have typically been short-term (4-6 weeks).[77] Even with longer term use, there is a reduced effect after 4-8 weeks.[78] Except for triazolam, these benzodiazepine hypnotics have long half-lives, which contribute to their efficacy for maintaining sleep, but also result in higher rates of next-day impairments, such as morning sedation, cognitive impairment, and motor incoordination.[79] Temazepam is the most commonly prescribed benzodiazepine hypnotic,[80] but, despite its long half-life, it appears to have minimal impact on number of awakenings, and produces tolerance, morning sedation, and cognitive impairment.[8] Triazolam, the only short half-life agent in this group, has more of an impact on sleep onset than maintenance, but possible amnestic effects have been a concern.[81,82]

Except in those with a history of substance abuse, abuse liability from these benzodiazepine hypnotics appears to be minimal.[83] However, due to concerns about abuse liability, the FDA has indicated that these medications should be limited to 7-10 days of use with reevaluation if used for more than 2-3 weeks. Some have argued that these limitations were based on now obsolete guidelines,[84] and that longer term use may not increase the risk for abuse liability,[85] but the long-term effects of these medications on tolerance and abuse liability require further study.

Nonbenzodiazepine hypnotics. Nonbenzodiazepine hypnotics are a new class of hypnotics that act on specific benzodiazepine receptor subtypes, but have a nonbenzodiazepine structure. Three nonbenzodiazepine hypnotics — zaleplon, zolpidem, and eszopiclone — have been approved by the FDA for the treatment of insomnia. As a class, these medications generally have shorter half-lives than their benzodiazepine predecessors, which results in greater effects on sleep onset than sleep maintenance and minimal morning sedation and other daytime impairments. Nonbenzodiazepine hypnotics also may have less abuse liability potential than benzodiazepine hypnotics, although further research is needed.[86]

Zolpidem is the most commonly prescribed agent for insomnia,[80] and due to its rapid onset and short half-life (1.5-4 hours), it has more of an effect on sleep onset than sleep maintenance.[87] Modified-release formulations may provide better sleep-maintenance effects, but data on these formulations are still needed.[88] Efficacy data do not extend beyond 1-2 months, so the effects of longer term use are unknown.[89]

Zaleplon has a very short half-life of only about 1 hour and, therefore, affects primarily sleep onset.[90] Higher doses may affect sleep maintenance and may increase the risk for side effects.[91] Although studies of zaleplon have been of longer duration than zolpidem, long-term safety and efficacy beyond 1-3 months have not been established.[92,93]

Eszopiclone is the newest medication in this group, and it has the longest half-life (5-6 hours). Studies show that this half-life appears adequate to produce effects on sleep maintenance as well as sleep onset while also resulting in minimal morning sedation.[94,95] Eszopiclone does not have a limitation on duration of use, and recent findings have shown efficacy and safety with minimal tolerance or abuse liability over 12 months of use.[96]

As a group, these medications appear to produce minimal sedation effects or psychomotor impairment.[97,98] These reduced side effects relative to benzodiazepine hypnotics appear to be due to their short half-lives more so than their selective receptor agonist effects.[99] Nonbenzodiazepine hypnotics also may produce potentially fewer or less severe drug interactions than many of the benzodiazepine hypnotics because they rely less exclusively on CYP3A4 metabolism.[100] Substantial proportions of these medications, however, are still metabolized through CYP3A4; so these medications, as is the case with the most traditional benzodiazepine hypnotics, should be carefully monitored if CYP inducers (rifampicin) or CYP3A4 inhibitors (ketoconazole, erythromycin, and cimetidine) are also being prescribed.[100] Alcohol also potentiates the effects of all hypnotics, so patients should be instructed not to drink, and if they do, to understand that they will feel more sedated the next morning, potentially affecting their ability to drive.

Medications for insomnia are typically taken every night on a prophylactic basis to manage insomnia. Due to the rapid onset and minimal abuse liability of nonbenzodiazepine hypnotics, nonnightly or as-needed use has been considered and appears safe and efficacious in preliminary trials.[101] Further trials, however, are needed to substantiate the safety and efficacy of long-term, nonnightly administration.

Nonbenzodiazepine hypnotics have shorter half-lives, which result in greater effects on sleep onset than sleep maintenance and minimal morning sedation and other daytime impairments. They may also be associated with fewer or less severe drug interactions, and may have less abuse liability than benzodiazepine hypnotics.

Discontinuation of hypnotics. Little research has been conducted on the persistence or reappearance of symptoms after prescription therapy is discontinued. Discontinuation of hypnotics, whether benzodiazepine or nonbenzodiazepine, generally results in relapse of symptoms. Many of the benzodiazepines also produce rebound insomnia, insomnia that is worse than pretreatment levels, for a few days. Rebound insomnia also may be reduced with the newer nonbenzodiazepine hypnotics, although further research is needed.[78] CBTI has been used to reduce relapse rates after benzodiazepine discontinuation.[102]

Melatonin receptor agonists. The FDA recently approved ramelteon for the treatment of chronic insomnia. Ramelteon is a selective melatonin receptor agonist (MT1, MT2) that is rapidly absorbed (< 1 hour) and has a relatively short half-life (2-5 hours). Initial studies of ramelteon have shown reduced sleep-onset latency compared with placebo, with a low rate of side effects and adverse events.[103] Abuse liability also appears to be minimal. Ramelteon should not be prescribed concomitantly with strong CYP1A2 inhibitors, such as fluvoxamine. Although ramelteon is a promising alternative to sedative-hypnotics, further research on its safety and efficacy, particularly long-term, is needed.

Prescription Drugs Without FDA Approval for Insomnia

Trazodone is one of the most commonly prescribed medications for the treatment of insomnia, comparable to zolpidem.[80] The low cost of antidepressant medications along with unrestricted long-term use and minimal abuse liability may be factors leading to the increased use of these medications for insomnia.

Trazodone is sedating, but there is a paucity of data on its effects on insomnia. Research has usually been performed with small, comorbid, depressed samples with short and equivocal effects on sleep.[104,105] Trazodone can have significant side effects, including orthostatic hypotension, blurred vision, nausea, dry mouth, constipation, drowsiness, headache, and (rarely) priapism. These side effects also increase the risk for falls and accidents, which can have serious consequences in the elderly. Although these risks are less pronounced at the lower doses typically used for insomnia, the risk-benefit ratio may be too great in some situations to use trazodone for insomnia.[106] There are also limited data on the short-term effects of doxepin[107] for insomnia. The potential adverse effects from trazadone, doxepin, and other antidepressants overshadow the limited efficacy data on these medications. Dose-response relationships of antidepressants for insomnia also are poorly understood.[108,109]

The SOS Conference Statement notes that various other medications have been used in the treatment of insomnia, including barbiturates (phenobarbital) and antipsychotics (quetiapine and olanzapine). These medications, however, have serious side effects and adverse risks with little to no data supporting their efficacy. Therefore, these medications are not recommended for the treatment of insomnia.

According to the SOS Conference Statement, the risk-benefit ratio may be too great in some situations to use trazodone or other antidepressants for the treatment of insomnia. In addition, barbiturates (phenobarbital) and antipsychotics are not recommended for the treatment of insomnia.

Over-the-Counter Medications

Over-the-counter (OTC) medications are frequently used for insomnia. About one fourth of US adults with sleep difficulties use OTC sleep aids.[110]

Antihistamines (H1 receptor agonists, such as diphenhydramine) are the most commonly used OTC medications for insomnia. There is, however, no systematic evidence of efficacy for insomnia, and there are significant side effects, including dry mouth, blurred vision, urinary retention, constipation, and a risk for increased intraocular pressure in patients with narrow angle glaucoma.[111]

Alcohol is often used to reduce sleep-onset latency. Although alcohol does reduce sleep latency, it also results in poorer quality sleep and nighttime awakening. Alcohol also is clearly not appropriate for someone with a risk for substance use. Therefore, alcohol cannot be recommended as a sleep aid.[112]

Melatonin is a natural hormone that is produced by the pineal gland that has a role in circadian rhythm control. Melatonin may be helpful for reducing symptoms of jet lag, but there is minimal evidence of efficacy for insomnia. Melatonin appears to be safe for short-term use, but long-term safety is unknown. Except for the recently FDA-approved ramelteon, melatonin compounds are unregulated, and preparations may vary.[113]

L-tryptophan is an endogenous amino acid sometimes used as a hypnotic. Evidence of efficacy for insomnia, however, is extremely limited and there are possible toxic interaction effects with some psychiatric medications.[114]

Valerian is derived from the valeriana plant root and thought to promote sleep, but there is no proven benefit for insomnia. Valerian is unregulated and possibly associated with hepatotoxicity. Other herbal products are sometimes used for insomnia, but there are no data supporting their efficacy and there are similar concerns about safety and drug interactions.[115]

Other alternative treatments, such as tai chi, yoga, acupuncture, and light therapy, have been used to treat insomnia, but they have not been adequately evaluated.[114,116]

OTC products, alternative treatments, and complementary therapies are often used to treat insomnia. These therapies, however, have not been systematically evaluated; efficacy data are lacking; and there are concerns about side effects.

Case Study: Part 3

Following the clinical assessment, the patient is advised regarding treatment approaches. Although menopausal symptoms appear to have been a precipitant of the insomnia, these symptoms have resolved and no longer appear to be related to the insomnia. The patient is counseled about cognitive behavioral and sedative-hypnotic approaches for insomnia. Given the minimal risks, she would prefer to try CBTI first, but the nearest specialist with expertise in CBTI is 2 hours away. Therefore, she agrees to try one of the newer sedative-hypnotics and to obtain an abbreviated form of CBTI from the nurse practitioner who has some limited training in this approach.

Because she presents with both sleep-onset and sleep-maintenance difficulties, and may require long-term medication use to control her insomnia, she is started on an agent appropriate for long-term administration immediately before bed each night, and advised that it may be necessary to increase her prescription if her sleep difficulties, particularly sleep maintenance difficulties, persist.

The patient meets with the nurse practitioner who provides information about sleep hygiene and instructs her to refrain from using alcohol to fall asleep, particularly in combination with her medication. A consistent wake time of 7:00 am is agreed to and a time to bed of 12:30 am is determined based on her average time asleep from her sleep diaries. The patient is concerned that she may be more tired than usual if she goes to bed this late, but is reassured that she will be getting the same amount of sleep as she usually does, just more consolidated. She is also instructed to get out of bed if she does not fall asleep within 15 minutes, to do something restful, and then return to bed when she feels sleepy again. She is assured that she can function adequately the next day if she does not get much sleep, which she has been doing for years, and that she can only control getting in and out of bed, not if and when she falls asleep while in bed. She is encouraged not to take naps and to maintain her regular wake time even if she did not sleep well the night before or can sleep later that morning.

After 2 weeks, the patient’s sleep diary shows that she has generally adhered to her new sleep schedule and that her sleep efficiencies are above 90% as a result of her bedtime restrictions. She is instructed to adjust her bedtime 15 minutes earlier and to readjust her bedtime earlier each week if her sleep efficiencies average above 90%. She is encouraged to continue the strategies that appear to be working, particularly maintaining a consistent bedtime, not taking naps, and getting out of bed if she is unable to fall asleep.

At a follow-up visit 1 month later, the patient reports sleeping well and feeling rested although her total sleep time is only 7.5 hours, less than she thought was adequate. She is reassured that sleep needs change over time and that her sense of feeling rested and restored is more important than how much sleep she gets. She is encouraged to continue the CBTI strategies that she has found helpful thus far. She wonders whether the medication is still needed to control her sleep. She is instructed to shift from taking it every night to taking it as needed after getting out bed if she is unable to fall asleep within 15 minutes.

At a follow-up visit 3 months later, the patient reports that she no longer takes the medication for sleep, that she continues to get about 7.5 hours of sleep per night with little to no difficulty initiating or maintaining sleep, and that she feels rested and refreshed most mornings.

What Are Important Directions for Insomnia-Related Research?

Based on what is known about the manifestations and management of insomnia, the SOS Conference Panel made a number of recommendations for future research needs:[9]

  1. Developing and validating instruments to assess chronic insomnia, particularly measures of outcome and diurnal consequences;
  2. Conducting more research on possible genetic and neural mechanisms of insomnia;
  3. Conducting longitudinal observational studies to better understand the incidence, course, and correlates of insomnia, including the adoption of sleep-disturbance items in national health survey research;
  4. Obtaining more information on the impact of insomnia on quality of life and the indirect and direct impact on individuals, caregivers, and society as a whole;
  5. Providing better estimates of the cost of illness to determine cost-effectiveness of treatments;
  6. Obtaining more long-term outcome data, particularly following discontinuation of treatment;
  7. Performing large-scale, multisite comparative treatment trials, including studies of the efficacy of combined or sequenced administration of medications and CBTI;
  8. Conducting more research on OTC and alternative remedies for insomnia;
  9. Conducting efficacy trials in subpopulations, such as children, nursing home residents, and postmenopausal women, and in those with comorbid as well as primary chronic insomnia; and
  10. Assessing clinician decision making with insomnia patients; although much is known that can inform clinical decision making, much more research is needed in this area.

Conclusions

Insomnia is a major public health problem affecting millions of individuals, their families, and their communities. Little is known about etiologic mechanisms, but hyperarousal, cognitive processes, and behavioral conditioning have some support as possible factors. Current evidence supports the efficacy of CBTI and sedative-hypnotics for the treatment of insomnia. Despite widespread use, there is very little evidence supporting the use of other treatments, such as antidepressants and OTC agents, for the treatment of insomnia.

Although there are a number of efficacious medications for insomnia, the SOS Conference Panel noted concern about the mismatch between the chronic, long-term nature of the disorder and the short duration of most clinical trials. Only eszopiclone has been evaluated in trials lasting 6-12 months. Newer medications not yet approved, such as indiplon (a short-acting nonbenzodiazepine hypnotic), provide additional options for the treatment of chronic insomnia, but there remains a clear need for new and more targeted drug therapies that can be used safely and effectively long-term. CBTI shows promising long-term effects with minimal safety concerns, and accessibility to this treatment option should be expanded.

References

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ADHD in Adults

In ADHD, Anxiety, Brain studies, School Psychology on Thursday, 13 September 2012 at 05:58

Unmasking ADHD in Adults

David W. Goodman, MD

http://www.medscape.org/viewarticle/768677

Adult ADHD

During the past decade, awareness has grown that ADHD is not limited to children and adolescents. Rather, ADHD is now recognized as a chronic neuropsychiatric disorder that persists into adulthood in up to 65% of children with ADHD.[1-3] Data from the National Comorbidity Survey Replication (NCSR) estimate that 4.4% of adults in the United States have ADHD, although as many as 75% have never been diagnosed and 90% remain untreated.[4,5] The many similarities in symptoms and impairments seen in ADHD and mood and anxiety disorders likely account for many of the misdiagnoses.[6] In addition, the rate of comorbidity in ADHD with mood and anxiety disorders, sleep disorders, and substance use disorders is high and further complicates accurate diagnosis.[5]

Current criteria for ADHD in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) were originally developed and validated for children.[7] Diagnostic criteria require an onset of symptoms before age 7 years; the presence of at least 6 of 9 possible symptoms in 1 or both of the 2 diagnostic clusters of inattentiveness and hyperactivity; and impairment in 2 or more settings (such as home, school, and work).[7] Many similarities exist in the presentations of childhood and adult ADHD; however, adults are more likely to present with symptoms of inattention than hyperactivity.[8] But the presence of childhood symptoms is necessary for a diagnosis of ADHD in an adult.

Clinicians can use several screening tools to help in the ADHD diagnostic process; however, high scores on these tools must be interpreted within a clinical context following a clinical interview. For example, a high score on the ASRS may suggest ADHD[9,10] but may also be the result of acute anxiety, acute depression, or active substance abuse. Patients who take online screeners and self-diagnose ADHD present their symptoms and “diagnosis” to their clinicians in a descriptive rather than a diagnostic context, not understanding how other possible psychiatric disorders may lead to high screening scores. As a result, their self-diagnoses are typically inaccurate.

The clinical interview includes a comprehensive patient history that covers all major psychiatric disorders. The clinician reviews the presenting symptoms in a diagnostic evaluation, inquiring about other possible psychiatric disorders that the patient may not include in the description of symptoms. Through this process, the clinician can rule out primary mood or anxiety disorders (among others), and also ascertain a longitudinal course of symptoms originating during childhood to confirm a diagnosis of ADHD. An accurate account of childhood symptoms of ADHD improves if corroborative historical information can be obtained from an outside informant (for example, a parent). This historical information can be obtained by having a parent complete a childhood ADHD symptom rating scale that can be returned to the PCP. The use of an outside informant also conveys to the patient that third-party information will be used to establish an accurate diagnosis, a disincentive to those who simply seek a prescription for stimulants.

ADHD vs GAD

The cognitive and affective symptoms of ADHD can be similar to those of other psychiatric disorders, most notably mood and anxiety disorders. However, specific distinguishing characteristics can assist with the differential diagnosis. In this case, despite reporting current symptoms that might be consistent with ADHD, the notable absence of ADHD symptoms during Ms Jones’s childhood and adolescence precludes a diagnosis of ADHD. A more accurate diagnosis is generalized anxiety disorder (GAD), which is characterized by excessive anxiety and worry that is difficult to control and is associated with at least 3 of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance, which cause clinically significant distress or functional impairments.[7] Significant chronic anxiety exacerbated by an acute, stressful event can produce cognitive symptoms that appear similar to ADHD. Remember: patients use psychological terms descriptively, not diagnostically.

A survey of 400 primary care physicians highlighted the challenges clinicians face when diagnosing ADHD in adults.[11] Approximately two-thirds of the participating respondents referred adults with possible ADHD to specialists for diagnosis and treatment, whereas they felt more competent and confident when diagnosing depression or GAD. Surveys find that only 2% of PCPs refer patients to specialists for the diagnosis and management of depression; for GAD, only 3% refer out.[11,12]

ADHD and Comorbidity

ADHD affects approximately 9 to 10 million adults in the United States (4.4% of the adult population). This makes ADHD in adults the second most prevalent psychiatric disorder after major depressive disorder (MDD), which reportedly affects 6.6% of the US population, and more prevalent than GAD (3%), bipolar disorder (2%), and schizophrenia (1%).[5] Adults with ADHD have a higher percentage of comorbidities than their peers without ADHD.[5] Among the most prevalent psychiatric comorbidities in patients with ADHD are anxiety disorders, mood disorders, and substance use disorders (SUD).[13] Many adults with ADHD present with symptoms of anxiety, MDD, or both. Further, high levels of stress may mimic the symptoms of ADHD.[13] Consequently, the high prevalence rate of ADHD in the adult population makes it essential for clinicians to include ADHD as part of the differential diagnosis in any mental health evaluation or whenever patients present with depression or anxiety.

Data from the NCSR suggest that up to 75% of adults with ADHD were not diagnosed during childhood.[5] Many adults play down a possible diagnosis of ADHD because they do not recall being hyperactive in childhood or because they have not been previously diagnosed with the disorder. Other adults will dismiss the diagnosis because they appear to be functioning well and are successful in their chosen fields, even though they have symptoms such as restlessness, low self-esteem, or poor time-management skills.[14] Exceptionally intelligent individuals or adults who had predominantly inattentive ADHD as children may not have had observable impairments during childhood because disruptive behavior was absent; however, symptoms may surface as demands increase with greater school and work responsibilities.[15] Similarly, clinicians may overlook ADHD among high-functioning patients, not realizing the need to look past a patient’s success to explore whether the patient might have developed strategies to compensate for ADHD-related deficiencies and is working hard to compensate.

PCPs who rely on the accuracy of a psychiatric diagnosis of adult ADHD from mental health clinicians may not serve their patients well. Data from the NCSR indicate that 37% of women and 53% of men later diagnosed with ADHD were currently taking or had been in treatment for other mental disorders or SUDs in the previous year, in contrast to 25% who had been treated for ADHD.[5] From these data, Kessler and colleagues concluded that adult ADHD is often misdiagnosed by mental health providers.[5] Before prescribing medication, the PCP should review the psychiatric presentation and history with the patient to ensure agreement on the diagnosis. Premature prescription of stimulants for ADHD will only cloud the diagnosis, as adults with ADHD, as well as people in general, may report improvements in mood, cognition, and energy when taking stimulants, which does not confirm a diagnosis of ADHD. In addition, undetected psychiatric disorders may worsen in the presence of stimulants prescribed for ADHD.

Strict adherence to the DSM-IV-TR diagnostic criteria might lead to substantial underdiagnosis of ADHD, as these criteria were originally developed for young boys and may not reflect ADHD symptoms in adults.[16] Clinicians may need to examine whether the patient is advancing appropriately in his or her career or has become a workaholic to compensate for disorganization, procrastination, and sloppy errors.[17] Recent research highlights that adults with ADHD often underestimate the degree of ADHD-related impairments.[18] ADHD that persists into adulthood has been associated with many adverse life experiences or outcomes, including divorce, substance abuse, motor vehicle infractions, academic and occupational underachievement, and brushes with the law.[5,16,19-24] Research suggests that although the number of symptoms may decline along the lifespan, the severity of the impairments does not.[25]

Among the numerous medical conditions that may be associated with cognitive symptoms similar to those of ADHD are thyroid disorders, sleep apnea, hypoglycemia, and lead poisoning.[13] The prevalence of psychiatric comorbidity associated with ADHD is high, with 1 large study reporting that 87% of adults with ADHD had at least 1 comorbid psychiatric diagnosis and 56% had at least 2 comorbid psychiatric disorders.[25] Common comorbidities in ADHD include GAD (which occurs in 25% to 43% of the adult population with ADHD), MDD (16% to 31%), bipolar disorder (up to 47%), and SUD (21% to 53%).[26-28]

Differentiating ADHD and Other Psychiatric Disorders

Clinicians often mistake adult ADHD symptoms as manifestations of other psychiatric disorders, especially anxiety, MDD, or bipolar disorder.[29] It is especially important that clinicians attend to the context of the symptoms: when they originated, how long they have persisted, and whether aggravating or alleviating factors exist. Clinicians also need to determine whether the symptoms might be a function of stress or another condition, such as a sleep disorder. Patient misinterpretation of the symptoms may be more prevalent among adults who were not diagnosed with ADHD during childhood, and some adults may be surprised that they did not “outgrow” their childhood ADHD. Other adults may not recall being diagnosed with ADHD during childhood, suggesting that the absence of a self-report of an ADHD diagnosis may not accurately reflect the absence of childhood ADHD.[30] Misdiagnosis and subsequent inappropriate treatment may help to resolve some secondary symptoms (anxiety and minor depression) but will not resolve the core symptoms of inattentiveness, impulsivity, and hyperactivity.

ADHD is historically a disorder of childhood; as such, diagnosis requires evidence of symptoms occurring during childhood. Adults typically present with fewer overt symptoms and different manifestations of hyperactivity, inattention, and impulsivity than children (Table 1).[31] Whereas hyperactive children cannot sit still and are fidgety, adults may feel restless, have difficulty relaxing, and show impatience. Childhood manifestations of inattention include daydreaming, poor reading comprehension, and working slowly; adult manifestations include procrastination, disorganization, forgetfulness, and missing or showing up late for appointments. Making careless mistakes is common among patients of all ages with ADHD. Impulsive symptoms during childhood include blurting out answers, interrupting others, and having temper outbursts; adults will also manifest with temper outbursts and verbal impulsivity, as well as impulsive spending, starting but not necessarily finishing multiple projects, and moving from job to job.[31]

Table 1.

ADHD Symptom Evolution from Childhood to Adulthood

Childhood Adulthood
Inattention
  Difficulty sustaining attention (meetings, reading, paperwork)
Failure to pay attention to details Makes careless errors
Appears not to listen Easily distracted/forgetful
Lacks follow-through Poor concentration
Cannot organize Difficulty finishing tasks
Loses important items Disorganized/misplaces items
Hyperactivity
Squirming/fidgeting Inefficiencies at work
Cannot stay seated Internal restlessness
Cannot wait his/her turn Difficulty sitting through meetings
Runs/climbs excessively Works more than one job
Cannot play/work quietly Works long hours
“On the go”/seems “driven by a motor” Self-selects very active jobs
Talks excessively Overwhelmed
Talks excessively
Impulsivity
Blurts out answers Impulsive job changes
Cannot wait in line Drives too fast
Intrudes/interrupts others Interrupts others
Easily frustrated

The Question of Early Symptoms

A particularly challenging component in diagnosing adult ADHD is obtaining sufficient retrospective information to confirm the presence of ADHD symptoms during childhood. Patients may not remember having ADHD-related symptoms before age 7 (a diagnostic criterion for pediatric ADHD in the DSM-IV-TR), although they may identify problems in late grade school or early middle school that continued throughout high school. A recent study compared 4 groups of adults: those who met all criteria for childhood-onset ADHD; those who met all criteria except the age-at-onset criterion (late-onset ADHD); those with subthreshold ADHD who did not meet full symptom criteria; and those without ADHD.[32] Substantial similarities existed between the adults who met the age-at-onset criterion and those with late-onset ADHD, leading these and other investigators to conclude that the current age-at-onset criterion of 7 years is too stringent and to suggest extending the criterion to age 12 in the next iteration of the DSM.[32,33]

Many adults who were not diagnosed during childhood have developed compensatory mechanisms enabling them to function, albeit less than optimally. Clinicians could ask to speak with the patient’s parents or other family members who may be able to provide insights into the patient’s childhood symptomatology. Similarly, current family members, a spouse, and friends might report clinically relevant ADHD symptoms that have been observed for a long time. While an adult might recognize restlessness as a possible ADHD symptom and admit to receiving numerous driving citations, others might note that the patient overreacts, has difficulty staying with tasks, is easily frustrated, or has held numerous jobs.

No standard for the screening of adults for ADHD currently exists. Among the tools that clinicians can use to help in the diagnostic process are the 18-item World Health Organization’s (WHO) ASRS, which can be freely downloaded from the Internet[34]; the Conners’ Adult ADHD Rating Scale (CAARS); the Brown Attention Deficit Disorder Scale (BADDS); the Wender Utah Rating Scale; and the Wender-Reimherr Adult Attention Deficit Disorder Scale. A recent factor analysis determined that many of these scales are in strong agreement with one another, suggesting that clinicians can choose whichever scale is the most pragmatic, cost efficient, and least time-consuming to use.[35] Patients who screen positive on these assessments should then undergo a full diagnostic evaluation, including a clinical interview that assesses current and lifetime symptoms, a thorough developmental history, and behavioral assessments to identify any functional impairments and symptoms.[31]

Treatment of ADHD in Adults

As yet, no formal guidelines have been developed for the treatment of adult ADHD in the United States. However, guidelines for the treatment of ADHD in children and adolescents, as well as international guidelines for the treatment of adult ADHD, offer recommendations that can be extrapolated to US adults. Considerable concordance exists among the guidelines established by the Canadian ADHD Resource Alliance (CADDRA),[17] the American Academy of Child and Adolescent Psychiatry (AACAP), the National Institutes of Health (NIH), and the British Association for Psychopharmacology on Childhood ADHD.[36] The National Institute for Health and Clinical Excellence (NICE) guidelines address both childhood and adult ADHD.[37] The European Network Adult ADHD consensus statement on the diagnosis and treatment of adult ADHD notes the substantial negative and far-reaching consequences of non-treatment of ADHD.[38] These guidelines recommend a multimodal approach to the treatment of ADHD in adults, beginning with psychoeducation about ADHD and pharmacotherapy for ADHD and any comorbid disorders. Recognizing that pharmacotherapy is often insufficient to address all the problems associated with adult ADHD, the guidelines recommend various symptom-specific coaching programs and cognitive behavior therapy to teach problem solving, coping, and time management skills.[38] Similar multimodal treatment recommendations have been proposed by CADDRA.[17]

Available pharmacologic treatments include short-acting and long-acting stimulant and nonstimulant medications. Psychostimulants, including amphetamines and methylphenidates, are recommended as first-line therapy for both children and adults across all sets of US and international guidelines. Currently, only long-acting agents have been approved for the treatment of ADHD in adults in the United States. Despite this, research suggests that 46% of adults diagnosed with ADHD are prescribed off-label, short-acting stimulants.[39]

Approximately 95% of children who were diagnosed with ADHD during childhood and treated with stimulants do not persist with their medication into adulthood,[40] perhaps because clinicians and patients continue to believe that ADHD is a disorder of childhood. Stimulant medications have been shown to effectively address many of the symptoms of ADHD, including poor attention span, restlessness, short-term memory, and hyperactivity. Some patients may respond preferentially to either amphetamine or methylphenidate compounds, and a small percentage of patients do not respond to stimulants at all.[41,42] Side effects are dose-dependent and can include insomnia, nausea, loss of appetite and weight loss, irritability, mood changes, and clinically nonsignificant increases in heart rate and blood pressure in the majority of patients.[43,44,45] However, clinical practice dictates monitoring vital signs to detect any clinically significant changes that may need to be addressed. A baseline check of vital signs also allows for the detection of undiagnosed hypertension that would require treatment before consideration of stimulant medication. Treatment should be initiated at a low dose and titrated based on symptom reduction and side effects. The dose response in adults is variable; clinicians should not expect that higher doses are needed because the patient is an adult or overweight.

US Food and Drug Administration (FDA)-approved nonstimulants in the ADHD armamentarium include atomoxetine, extended-release (XR) guanfacine, and extended-release (ER) clonidine. Only atomoxetine is currently approved for use in adults, while guanfacine XR and clonidine ER have been approved for use in children and adolescents up to age 18. Other agents that are used off-label include bupropion, tricyclic antidepressants (especially desipramine), and modafinil. The onset of action for atomoxetine is slower than for stimulants, taking to a few weeks to attain the maximum treatment effect. The lack of an abuse potential with nonstimulants may be particularly attractive for use in patients who have SUDs, are at risk for substance abuse, or are potential diverters or sellers of illicit substances.

Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. It has been associated with slightly increased diastolic blood pressure and heart rate, and patients with milder forms of autonomic impairment should be monitored if given this agent.[46] In addition, atomoxetine is predominantly metabolized by the cytochrome P450 2D6 (CYP2D6) isoenzyme, necessitating caution for patients who take medication that inhibits CYP2D6, including fluoxetine, paroxetine, and bupropion.[13] Guanfacine is a direct agonist of the α-2a subtype of norepinephrine receptors. Guanfacine XR can be used as monotherapy or adjunctive therapy with a long-acting psychostimulant.[47,48] Clonidine ER is an α-2a-adrenergic receptor agonist that is considered a second-line agent in the treatment of ADHD, but it may be particularly useful for patients with ADHD and comorbid Tourette syndrome or other tic disorders. As yet, the α-2a agonists have not been studied sufficiently in adults either as monotherapy or as adjunctive treatment in combination with stimulants. Because of the effects of these agents on blood pressure and pulse, monitoring vital signs is recommended, and caution is needed in adults who are being treated for hypertension with other medications.

Monitoring Effects and Side Effects After Initial Treatment

Routine clinical monitoring is necessary throughout the duration of treatment.[13] It is important to meet with the patient on a more frequent basis after medication has been initiated to review tolerability and efficacy and to adjust the dosage (or the medication) as necessary; this typically requires follow-up every 2 to 3 weeks and availability by phone if the patient encounters problems with the medication or dosage. Patients engaged in psychotherapy or skills training will likely be seen on a more frequent, often weekly or biweekly, basis. Once stabilized on an effective and well-tolerated dosage of medication, patients can be seen every 2 to 3 months to monitor the need for dosage adjustments based on tolerability and residual symptoms. Clinicians should assess ADHD symptoms, medication side effects, medication adherence, and comorbid medical/psychiatric conditions at each visit. Similarly, clinicians should monitor caffeine and nicotine intake, as these will further elevate blood pressure and heart rate for all patients on ADHD pharmacotherapies. Although not a common problem, patients with a low body mass index (BMI) should be monitored for suppressed appetite leading to weight loss. Regular assessment of medication utility as measured by daily functional performance should be part of routine monitoring. In the process, you can discuss the continued benefit of medication with the patient. On occasion, a patient may wish to stop the medication to reassess its benefit, and the physician should provide support and oversight in this process. A follow-up reassessment when the patient is off the medication can clarify the re-emergence of ADHD symptoms and impact on daily productivity.

One means for monitoring symptom reduction is through the periodic use of symptom checklists, such as the patient-rated 18-item ASRS. The ASRS is an easy and preferred tool to use because it is standardized, validated, nonproprietary, and readily available on the Internet. It can be administered at baseline and then intermittently, especially with changes to medication dosage, to complement the clinical interview. Patients and their clinicians can get a sense of ADHD symptom improvement with treatment or an increase in symptoms if treatment is suspended or stopped. Patients may forget their ratings of baseline symptoms and find the change in symptom ratings helpful to verify treatment benefit. Although symptom reduction is desirable, the true measure of treatment benefit is the improvement in daily function, such as the ability to initiate and complete more tasks, sustain attention, be less distractible in conversations and meetings, finish tasks on time, reduce careless oversights and errors, and have better, more patient social interactions.

Stimulants, Nonstimulants, and Cardiovascular Risk in Adults

Stimulants are associated with mild elevations in both blood pressure and pulse. It is recommended that patients receiving stimulants have blood pressure and heart rate checked at baseline and regularly throughout treatment.[49] A retrospective database analysis in the United Kingdom found no additional risk of sudden death associated with either stimulants or atomoxetine in children and adolescents 2 to 21 years of age with ADHD.[50] Another retrospective study of adults with new ADHD treatments found that preexisting cardiovascular conditions appeared more likely to reduce prescribing of stimulant treatment in younger vs older patients but did not appear to influence initiation of atomoxetine therapy.[51] In this cohort of 8752 patients, 41% with 1 or more preexisting cardiovascular conditions were prescribed stimulants.[51] Small studies have demonstrated that adults being treated for primary essential hypertension can be safely treated with mixed amphetamine salts[52,53] and methylphenidate.[54] However, stimulant medications for ADHD should not be initiated until the patient is normotensive with a stable antihypertensive medication dose.

In 2008, in response to evidence supporting concerns that the use of stimulants for ADHD could augment the risk of serious cardiovascular events by increasing heart rate and blood pressure, the American Heart Association (AHA) recommended an electrocardiogram (ECG) before initiating treatment in children.[55] This recommendation contradicted recommendations by the AACAP and the American Academy of Pediatrics (AAP), which found that sudden cardiac death in persons taking stimulants was a rare event that could not be prevented or predicted by routine screening with ECG.[56] The AAP recommends an ECG only in those patients with the following risk factors: previously detected cardiac disease, palpitations, syncope, or seizures; a family history of sudden death in children or young adults; hypertrophic cardiomyopathy; or long QT syndrome.[56] Two recent large studies found no significant additional risk of sudden death, myocardial infarction, or stroke in children, young adults, or middle-age adults who were receiving stimulants or atomoxetine.[45,57]

Clinical trials of ADHD medications demonstrate short-term efficacy and safety; however, the majority of patients require chronic long-term treatment.[58-60] Recent studies have demonstrated the safety and efficacy of stimulants, atomoxetine, and guanfacine XR over 24-month treatment periods in children and adolescents.[61] Significant differences between stimulants regarding efficacy or risk of cardiac or cerebrovascular events are not apparent.[62] If clinicians observe any cardiovascular changes, they should determine whether these changes are directly related to the ADHD medication or might instead be related to cardiovascular risks and changes associated with normal aging — for example, weight gain as a cause of hypertension. Nevertheless, long-term studies addressing adverse events are warranted.[59]

Approaches to Improve Executive Function in Adults With ADHD

ADHD can be associated with executive function impairments that can compromise occupational functioning.[63] Executive function is broadly defined as the ability to organize, sequence, prioritize, and hold information in your memory as you consider multiple factors (working memory). Executive function can be defined behaviorally (symptoms observed by patient or others) or by specific neuropsychological measures. Most ADHD symptom checklists enumerate executive function symptoms because they are part of the ADHD symptom criteria. By this definition, all patients with ADHD have executive dysfunction. Executive function may improve with ADHD medication such that inattention, distractibility, and sustained attention improve. In this case, executive dysfunction may be an epiphenomenon of inattention, distractibility, and restlessness. Adults with ADHD may notice improvements in many of their symptoms of impulsivity, inattention, and restlessness but may still struggle with difficulties in organization, developing timelines, planning, and making and initiating decisions.

If the definition of executive function is based on abnormalities that appear on specific neuropsychological tests, then approximately one-third of ADHD patients have executive dysfunction, not 100% as the behavioral definition demands.[64] The clinical relevance of these distinctions is that patients with ADHD may have improved attention and less distractibility and restlessness but still be disorganized. If the clinician believes the disorganization is a residual ADHD symptom, the clinician may respond by increasing the dose of ADHD medication, only to find no further benefit but more side effects. These residual executive dysfunction symptoms tend not to improve with escalating medication dosing.

Results from 2 large trials indicate that adults with ADHD who experienced improvements in executive function with stimulant treatment also experienced improvements in health-related quality of life, particularly in the domains of performance and function.[65] However, a clinical trial of adults with ADHD found that the presence of executive function deficits, as assessed by standardized neuropsychological testing, did not affect clinical response to treatment with osmotic controlled-release oral delivery system (OROS) methylphenidate, and that measures of executive function were not affected by treatment response.[66] The need to better define executive function deficits so that an accurate assessment can be determined is critical; the means to minimize such impairments can be challenging.

Some patients might benefit from adjunctive therapy to address executive function deficits. Research in children and adolescents suggests that the concurrent use of stimulant and nonstimulant therapies can afford significantly greater improvements in ADHD symptoms than stimulant monotherapy, although some combinations have been associated with an additive adverse effect burden and higher cost.[67;48]

Many clinicians recommend cognitive behavior therapy (CBT) or other forms of psychotherapy once the patient has been stabilized on pharmacotherapy. CBT and other interventions can help the patient address organization skills and self-efficacy that have evolved over many years of insufficient treatment for ADHD; it can help patients develop effective compensatory strategies and improve other functional impairments typically associated with ADHD.[68,69] CBT may also help the subset of patients who choose not to use medications (or for whom medications are not appropriate or intolerable), as well as the large proportion of patients who have comorbid conditions.[70] Research suggests that adding CBT may enhance the response to and benefits of pharmacologic treatments.[68]

Metacognitive therapy uses principles and methods of CBT to teach time management, organization, and planning skills, and to address depressive and anxious thoughts that undermine effective self-management. Solanto and colleagues[71] compared a 12-week course of group metacognitive therapy (N = 41) with supportive therapy (including nonspecific group support and validation, psychoeducation, and therapist attention; N = 38) in adults with ADHD. They found that metacognitive therapy provided significantly more benefit in adults with ADHD “with respect to inattention symptoms that reflect the specific functions of time management, organization, and planning.” These benefits were seen in patients who were receiving medication treatment as well as those who were not.

When appropriate, patients may also benefit from couples or family counseling or both, and life skills training or coaching. A review of studies of group and individual psychosocial treatments for adult ADHD found that various psychosocial therapies, including skills-training and psychoeducation, improved motivation and reduced residual symptoms in adults with ADHD.[72]

ADHD and Substance Use Disorders

Up to 75% of adults with ADHD have had at least one comorbid condition,[13] and 40% of adults with ADHD present with a concurrent comorbidity.[73] The high rate of comorbid psychiatric conditions — particularly anxiety disorders, mood disorders, and SUDs — can influence both diagnosis and treatment of ADHD as well as the other condition(s). A significant number of adults with ADHD have a comorbid mood disorder, and a significant proportion of adults with mood disorders have comorbid ADHD.[74] As many as 50% of adult patients with ADHD have had comorbid SUDs.[23] Consequently, clinicians should maintain a high index of suspicion for ADHD among patients with any mental health concern because of its high prevalence in these subpopulations.[75,13]

Evidence suggests that ADHD is a significant risk factor for the development of both SUDs and cigarette smoking.[76] A recent meta-analysis and meta-regression analysis suggests that nearly 1 in 4 patients with SUD met DSM criteria for comorbid ADHD,[77] and 10% to 30% of adults with ADHD have SUD.[78] Alcohol dependence is associated with higher ADHD prevalence than cocaine dependence.[77] Substance use, including cigarette smoking, begins at an earlier age among adults with ADHD,[79] and SUDs are generally more severe in patients with comorbid ADHD.[16] Moreover, SUD may manifest with self-control, attention, and behavioral symptoms similar to those seen in ADHD. The prognosis for patients with ADHD and SUD worsens with additional comorbidities. Adolescents with ADHD and comorbid major depression generally have more severe substance use at baseline and throughout treatment compared with nondepressed adolescents with ADHD and SUD.[80]

Concerns that children treated for ADHD with stimulants are at elevated risk for developing SUD have not been supported by the research. A naturalistic, controlled, 10-year follow-up study of 112 boys and men over 10 years and found no statistically significant associations between stimulant treatment and alcohol, drug, or nicotine use disorders.[81] The investigators concluded that the risk for subsequent SUD is neither increased nor decreased in individuals treated with stimulants for ADHD during childhood and adolescence.

ADHD Comorbidity

It is estimated that only 25% of adult ADHD cases are uncomplicated.[26] In addition to SUD, ADHD has a high comorbidity with mood and anxiety disorders. Data from the NCSR indicate that 9.4% of adults with MDD have ADHD, as do 22.6% of adults with dysthymia.[5] The lifetime prevalence of anxiety disorders among adult patients with ADHD is 40% to 60%.[23] ADHD has been identified in 21.2% of adults with bipolar disorder,[5] and the presence of ADHD may increase the risk of developing bipolar disorder.[17] Many patients do not have just 1 comorbid diagnosis; diagnosing patients with SUD and comorbid psychiatric disorders can be particularly challenging because of the high rate of symptom overlap.

The numerous similarities in clinical presentation among these psychiatric disorders can interfere with accurate diagnosis. For example, symptoms of both ADHD and depression may include trouble sleeping, eating, and concentrating; patients with MDD, ADHD, or GAD may be restless and fidgety. It is important to obtain a comprehensive evaluation for child and adult symptoms, including the temporal relationship between the various comorbid disorders.[82] A primary complaint of a consistent negative mood for 3 months is more suggestive of MDD than ADHD, whereas a report of persistent poor concentration and lack of motivation dating from childhood is more consistent with ADHD. Poor concentration and anhedonia following a depressive episode suggests MDD; poor concentration, depression, organizational problems, and impulsivity that are long-standing suggest ADHD.[17] The clinical presentation of MDD is not affected by comorbid ADHD.[23] Clinicians need to distinguish between a lack of motivation suggestive of ADHD, dysregulated mood and irritability that might indicate ADHD with comorbid mood disorder, and significantly low affect symptomatic of depression.[17] The psychotic symptoms present in bipolar disorder are not likely to be misdiagnosed as ADHD; patients with ADHD do not report a cyclic pattern to their symptoms.[28] Primary care physicians who suspect bipolar disorder, or a manic or hypomanic episode, may want to refer the patient to a specialist, particularly if the patient is diagnosed with comorbid ADHD.

What to Manage First?

Identifying the primary disorder can be particularly challenging in adults with ADHD, as many comorbidities have an onset in mid-to-late-adolescence and these individuals have had many years of dealing with their disorders. In patients with active substance abuse, experts recommend that SUD be considered the primary diagnosis and treated first, regardless of age; once the SUD is under control, clinicians can then reassess the patient to determine whether the presenting symptoms were caused by the SUD, comorbid ADHD, or a mood disorder.[17,38] This strategy is based on controlled studies suggesting that treatment for ADHD in patients with comorbid active SUDs has little effect on either ADHD symptoms or substance use.[83] Adults with SUD who require treatment for ADHD cannot be treated with stimulants until they are in recovery treatment, as stimulants are contraindicated for patients who are actively using addictive substances. However, in adults with comorbid SUD, ADHD can be treated with FDA-approved nonstimulants such as atomoxetine or off-label bupropion, tricyclic antidepressants, or modafinil.[84] Stimulants, preferably long-acting formulations, can be used once patients are in stable substance use remission.

In adults, severe psychiatric mood or anxiety disorders are treated before treating ADHD, whereas ADHD is typically treated prior to initiating treatment for other psychiatric disorders of mild to moderate severity. In some cases, treating ADHD will help resolve the mild or moderate symptoms of the other psychiatric disorders. Clinicians must perform an adequate screen in adult patients with ADHD suspected of comorbid depression to rule out bipolarity. It is recommended that patients with comorbid bipolar disorder and ADHD be treated with mood stabilizers or atypical antipsychotics before initiating treatment with stimulants, which can destabilize bipolar symptoms.[85] Patients with comorbid ADHD and MDD can be treated with a stimulant and an antidepressant, particularly selective serotonin reuptake inhibitors (SSRIs).[74] Stimulants can be administered with serotonin-norepinephrine reuptake inhibitors (SNRIs), but this combination needs to be closely monitored for sympathomimetic side effects.[13] However, when atomoxetine is co-administered with SSRIs, one should be mindful of potential kinetic interactions through the cytochrome P450 enzyme system.

ADHD Treatment for Patients in Stable Recovery

Guidelines support and encourage treatment of ADHD in patients with SUD.[2,17,37,38] Indeed, optimal treatment for ADHD may improve adherence to treatment for SUD. Pharmacotherapy choices for adult patients in stable recovery can follow usual adult recommendations. Stimulants are more effective than nonstimulants for adult ADHD[86]; however, stimulants may be diverted or abused. These risks are lower for long-acting stimulants approved for adult ADHD (OROS methylphenidate, dexmethylphenidate XR, mixed amphetamine salts, and lisdexamfetamine) than for the short-acting agents.[83] At this time, atomoxetine is the only nonstimulant treatment approved for adult ADHD. The nonstimulant α-2 receptor agonists guanfacine XR and clonidine ER have not been studied in adults; their use is currently off-label in this population.

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Mastering anxiety

In Anxiety, Meditation, Mindfulness, Well-being on Sunday, 9 September 2012 at 05:58

Mastering Anxiety – By Dr. Neil Kobrin, Author of “Emotional Well-Being, Embracing the Gift of Life”

September 8, 2012

Retrieved from: http://drneilkobrin.com/mastering-anxiety/?goback=.gde_2047935_member_161038898

Anxiety is something everyone deals with, potentially on a daily basis. Some people encounter it more than others, and everyone deals with it differently. In order to master anxiety, one must be able to return to peace.

This reminds me of a great story of a monk from a monastery in the deep, back woods of India.

One day, the monk finds out that he’s going to be celebrated by the greatest master of his time. The master is going to visit the monastery and honor him with an award for all of the great work that he’s done in his lifetime. The monk is very flattered, and the whole monastery spends the entire day preparing for the master’s arrival. They clean and cook and get the whole place set up for this wonderful feast in honor of their monk. The master comes to the table and sits to the right of the monk and begins praising him for dedicating his life as someone who takes a vow to eliminate suffering for all beings.

The entire feast goes well, the master is very impressed. Soon, everyone is off to their individual chambers to sleep. That night, a disciple hears a sound by the windows and runs over to see what’s going on. He sees his master with a rucksack on his back heading out to the woods. The disciple climbs out of the window and runs up to his master and asks, “Where are you going, Master?” The master looks deeply into his disciple’s eyes and replies, “I failed today.” The disciple is confused. “What are you talking about, Master? Everybody honored you. It was beautiful.” The master looked at his disciple and reflected, finally saying, “That may be true my son, but just at the height of the ceremonies I looked down and noticed my palms were sweating. I have much work to do.” And so he went into the woods to sit in meditation and contemplation.

Now this story is confusing for some because it’s ending is ambiguous. That’s one of the things I like best about it, different people can interpret it different ways.

Similarly, mastering anxiety is done differently by different people. The monk was anxious, even while being praised by the great master. Perhaps it was because he was being praised by the great master and all of the preparation that went into the feast. Regardless, he was anxious and needed to return to his peaceful state. For him, meditation and contemplation worked. Perhaps they will also work for you.

Do you have a method you use to master anxiety and return to your own peaceful state?  Respond by commenting here, or feel free to join the conversation on my Linkedin Group http://bit.ly/MindfulMomentsGroup

Until next time, Dr. Neil Kobrin

 

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