Friday, April 08, 2005

What War Does

God does not play dice.  But American Presidents do, so long as it is someone's else's lives and money on the line.

WJR Awarded for Excellence*

News/Talk 760 WJR was recently awarded for excellence, receiving several recognitions from the Michigan Associated Press and the Michigan Association of Broadcasters. In addition, WJR was the ONLY Michigan broadcaster acknowledged in the regional Edward R. Murrow Awards competition.
*Gee, why don't I listen more often???
NPR is doing their fundraising thing this week.  Consequently, I've been listening to AM radio.  On 760 kilohertz -- WJR -- I've had the privilege of hearing Rush Limbaugh again. 

My first experience with Mr. Limbaugh occurred many years ago, late at night.  I had turned on the TV.  There was a talking head going on and on about liberals.  Literally, I though I had tuned in a late night parody, perhaps a rerun from Saturday Night Live.  After several minutes, I realized that, even as a parody, it was not really funny; the guy was just too offensive, even by SNL standards. 

The following day, I looked him up.  Only then did I realize that he's for real. 

Today, I learn that he is as offensive as ever.  One of the advertisements for his many newsletters starts out: "Want to give the left both barrels?  Subscribe to ..."  Apparently, you can get a special price by getting two different versions of his material. 

I guess you can brainwash both hemispheres of your cerebral cortex, for one low price!

"Give the left both barrels"???  That would appear to be a reference to a double-barreled shotgun.  Even if it were a parody, that would not be funny.  He's talking about shooting people because of their political beliefs.  Not funny.  In fact, I find it offensive.

During today's show, he got a call from US Army Captain David Rozelle.  The following is a bit from a prior interview (I can't get the transcript from today's show without paying money):
RUSH: And Brian Kilmeade then said, "What is your feeling about the operation in Iraq?"

ROZELLE: Success. When we had a successful election in Iraq, I felt good about my injury because I had contributed to something great. Those people, when it came out more than the American people came out to vote in a lot of senses, I mean it's great.
Today, it was more of the same.  The point they were trying to make, is that a lot of good things are happening in Iraq.  Mr. Limbaugh accused the Left of wanting things to go badly in Iraq, just to make Mr. Bush look bad. 

I don't know, maybe he's right about that.  The vast left wing conspiracy doesn't include me on the mailing list for their devious memoranda.   (I'm probably on their blacklist; when I was in college, there were liberal people who did not want to be friends with me, because I wasn't liberal enough.)

The point is this: there are many people who sit think the war was and is Iraq was a good idea.  Most American citizens think otherwise. 

The persons who think it was a good idea point to the abundant evidence of benefit: democratic elections, which someday made result in a government that actually works better than the one we destroyed; improving security forces, which someday might make people safer than they were before we invaded their country; the progress with reconstructing all the stuff we blew up, which might end up working better than what was there when the country was crippled by sanctions;  and all the other good stuff. 

The persons who think the war was a bad idea have an equally impressive list.  By one study, by the middle of 2004 there had been one hundred thousand excess civilian deaths since the onset of the war.  The number has been disputed, but I haven't seen anyone dispute the bottom line, which is that the death rate is higher now than it was before the war.  Starvation among children has increased from 4% to 8%.  That too has been disputed.  The UK says that child malnutrition has declined, from 17% to 12%.  Of course, if a country that we control has a 12% of its children malnourished, it is hardly flattering.  The health care system is in worse shape than it was before the war.  Tons of munitions that were not secured are now in the hands of bad people.  Fortunately, our government was mistaken about the existence of chemical and biological weapons, otherwise the country would really be in bad shape. 

If you look as those two lists: the benefits of the war, and the negative consequences, it is not obvious right away that one list outweighs the other.  Is there anything that can be added to either list, to tilt the balance more convincingly?

Sure.  The effects of the war are not limited to Iraq.  The United States of America has changed also.  There has been a redistribution of wealth.  Oil companies and defense contractors are making record profits.  Not content to squeeze money from the poor people of today, they are soaking the poor people of the next few generations, by running up a deficit.  That's a victory of sorts, for those Republicans who actually understand the predictable effects of their own policies.  Put that one in the "benefits" column.

Furthermore, the war has changed the stature of America in the eyes of the world.  Rather than acting as the World's policeman, we now are the World's loose cannon.  Other countries, those than might engage in oppressive practices, now must fear our might.  They cannot act with impunity, knowing that the World's policeman isn't paying attention.  They must fear us.  Unless, of course, they have something of value to trade for our tacit acceptance of their brutality.  Libya, Uzbekistan, and Ivory Coast are in that category.

I know I am wandering off the point, but I was listening to Rush Limbaugh earlier.  Blame him.

Getting back to a logical, orderly line of argument, let's agree that there are good and bad things about the war.  It is hard to look at the lists and see which is greater.  One reason for that is that the potential benefits still are exactly that: potential benefits.  The government is getting organized, but it remains unknown what will come of it.  Reconstruction is progressing, but at the current rate, it will take an awfully long time just to get the infrastructure back to where it was before the war.  The war may have influenced other countries to act in ways we find more acceptable, although that remains to be seen:  Lebanon could return to their former glory, or they could return to their former civil war. 

Furthermore, in a similar vein, the negative consequences of the war may turn out to be temporary.  Someone might get around to feeding all those starving kids.  Someone might rebuild the hospitals.  Someday they might have reliable electricity and potable water.  Someday all those things might result in improved life expectancy, reduced infant mortality, and so forth. 

With all that uncertainty on both sides, how can either side prove its point?  It's simple.  Neither can.  Nobody knows how this whole thing is going to end up, just as nobody knows what would have happened if we hadn't started this war.  In fact, not only do we have this uncertainty now, but the outcome was equally uncertain before the war.  We knew it might turn out well.  We knew it might turn into a big mess.

I guess this leaves us wondering: since you never know how a war will turn out, is there any circumstance that justifies a war?  Even in the best of circumstances, it always is a gamble.  Is there any situation in which it is justifiable to take that gamble?  We did take that gamble, and we still don't know whether it was worth it. 

We may never know.  However, we do know that the individuals who actually rolled the dice are richer now than they were before, and they are not suffering any of the consequences.  That's what war does, in the modern age.

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Wednesday, April 06, 2005

Pipeline Update: Eszopiclone in Pharmacies Now

Sepracor's new medication, Lunesta, was approved by the FDA last year.  I just heard that it is being shipped to pharmacies as of today.  I don't have a lot to add since my original post, although a couple more abstracts have appeared on Medline.  Also, I have a few comments about the potential for ancillary use of Lunesta in treatment of depression and chronic pain. 
Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia.
Zammit GK, McNabb LJ, Caron J, Amato DA, Roth T    
Curr Med Res Opin (2004 Dec) 20(12):1979-91       ISSN: 0300-7995

OBJECTIVE: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia.  The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia.

RESEARCH DESIGN AND METHODS: Patients (n = 308) were randomized to receive placebo or eszopiclone (2 mg or 3 mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo.  Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44).  Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST).

RESULTS: Eszopiclone 3 mg had significantly less time to sleep onset (p < or = 0.0001), more total sleep time and sleep efficiency (p < or = 0.0001), better sleep maintenance (p < or = 0.01), and enhanced quality and depth of sleep (p < 0.05) across the double-blind period compared with placebo.  Eszopiclone 2 mg had significantly less time to sleep onset (p < or = 0.001), more total sleep time (p < or = 0.01) and sleep efficiency (p < or = 0.001), and enhanced quality and depth of sleep (p < 0.05) compared with placebo, but did not significantly improve sleep maintenance.  There was no evidence of tolerance or rebound insomnia after therapy discontinuation.  Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group.  Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste.

CONCLUSIONS: Patients treated with nightly eszopiclone 3 mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial.  There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.
There is a blurb in Drugs in R&D about the product.  I won't copy the whole thing here, but I did find this bit interesting:
Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause.
Note that this could be taken to imply that eszopiclone has a significant role in treatment of depression.  The reference to the HAM-D17 refers to a rating scale (Hamilton, 17-item version) that is used to gauge severity of depression in the course of research studies.  The fact is, anything that helps a person sleep will result in an improvement on the HAM-D.  In order to really assess the significance of the study, we would need to see the mean changes in each item of the 17-item scale. 

From a clinical perspective, it is common practice to give a sleep aid in the acute phase of treatment of major depression.  Probably the most commonly-used drug in this context is trazodone.  Note that you can get a month's supply of trazodone for less than ten dollars.  I don't know the price of Lunesta, but I would guess that a month's supply is going to run in the $75-100 range.  Sure, if price were not a factor, I probably would rather give more patients Lunesta than trazodone -- the effect is more predictable -- but it would be hard to justify that as a routine practice. 

Most often, patients with depression and insomnia find that the insomnia resolves once the depression is controlled adequately.  For that reason, most of the prescriptions written in such a context are intended to be short-term interventions. 

What is more significant is the study with rheumatoid arthritis patients.  RA is a chronic, painful condition.  It is not desirable to use opiate pain killers to facilitate sleep in such patients, but sometimes that is the only option.  It would be good to have a nonopiate, nonaddicting, sleep aid that is suitable for long-term use in RA patients.  I would venture a guess, that Lunesta may establish a niche in the armementarium of drugs used for chronic pain patients. 

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Familial Advanced Sleep Phase Syndrome:
Exactly What is a Disease Anyway?

Lessons in Clear Thinking About Diagnosis and Labels

The news is not making much of a splash in the Blogosphere.  Scientists at the Howard Hughes Medical Institute, working on a condition known as Familial Advanced Sleep Phase Syndrome, have discovered the cause.  It is a mutant gene known as CKIdelta.  Their press release is here

FASPS is a condition in which people tend to fall asleep early in the evening, say around 5 PM, then awaken early.  They are healthy otherwise, and they sleep a normal amount of time.  For example, the person who goes to sleep every day at 5 PM may awaken every morning at 3 AM. 

In this post, I discuss the nature of FASPS and use that as a specific example, to illustrate certain general concepts about the diagnosis of illness, then explore what a diagnosis means in medical settings, as well as in society at large.
As for the affected individuals, Ptacek said most are able to live normal lives, and some are proud of being able to arise before dawn and get a lot done while everything is quiet. A few, however, are constantly bothered by living out of sync with everyone else's daily schedule.

“Some of them would never come to a doctor” to find out what's going on with their sleep pattern, Ptacek said, “because they aren't troubled by it. Often, they have adjusted and accommodated their jobs to match their ability. But others are bothered by being out of phase with the rest of the world.”

He said the FASPS subjects don't seem to sleep any more or less than other people; they just sleep at different times. And there is apparently no connection to the better-known problem called narcolepsy.
I first found the reference on Science Blog, but it also appears on Science News.  There are mainstream news articles here and here.  For some reason, it also was picked up by National Geographic News, here.  A few bloggers have written about it (1  2  3  4  5  6).   Most of the bloggers say things like, "See now I have an excuse." 

The medical establishment refers to the condition as a syndrome, not a disease.  In common usage, though, syndrome and disease are roughly synonymous.  When a person is diagnosed with a disease or syndrome, it has social significance.  For one, a person who is sick may be stigmatized.  On the other hand, in some instances, the person who is sick is excused from ordinary responsibilities, but may have alternate responsibilities instead.  This sometimes is referred to as the sick role:
The model of the sick role, which Talcott Parsons designed in the 1950s, was the first theoretical concept that explicitly concerned medical sociology.

In contrast to the biomedical model, which pictures illness as a mechanical malfunction or a microbiological invasion, Parsons described the sick role as a temporary, medically sanctioned form of deviant behaviour.
What interests me, at this time, is that sometimes it is not clear why a diagnosis will sometimes be stigmatizing, but at other times be deemed a valid excuse.  Note that, from a medical standpoint, all of this is superfluous.  Medical practice is in the business of making judgments about what is healthy, and what is not; to the extent possible, physicians should refrain from making judgments about whether a patient is good or bad, right or wrong, virtuous or despicable.  (This is hard to do; in my opinion, most physicians fail miserably; but that is another story.)  Physicians do have a role in making a judgment about whether a person should be excused from ordinary responsibilities on the basis of an illness.  That, however, is a judgment made about the impact of the illness, not a judgment about the patient.

Sometimes, the social consequence of a diagnosis changes over time.  For example, AIDS used to be horribly stigmatizing; these days, it is somewhat less so.  A similar transformation is occurring with some mental illness.  In cases of mental illness, though, the progress has been slow. 

There is a long history of change in the social consequences of a mental illness diagnosis.  In the 1960's and 70's there was a bit of a fad to consider mental illnesses not to be illnesses at all.  Rather, some thought that these conditions were nothing more than inappropriate labels that society put on persons who were merely different.  The classic work on this area, now discredited, was by Thomas Szasz: The Manufacture of Madness: A Comparative Study of the Inquisition and the Mental Health Movement.
Card catalog description [from Amazon.com]
In this seminal work, Dr. Szasz examines the similarities between the Inquisition and institutional psychiatry. His purpose is to show "that the belief in mental illness and the social actions to which it leads have the same moral implications and political consequences as had the belief in witchcraft and the social actions to which it led."
If you are tempted to think there might be some merit in Szasz's view, take a moment to read this article, about a person who received treatment at the University of Michigan's PsychOncology Program. 
ANN ARBOR, MI -For Bill Howe, cancer was a deep hole that went far beyond the physical effects of treatment. 

“With the combination of the treatments and the emotional rollercoaster that you ride when this happens to you, you get into a situation where you’re very confused, you’re lost, your anger is prevalent. You want answers and you can’t get them,” said Howe, 58, who was diagnosed with prostate cancer in 2001.

“It came to a point where I just couldn’t do it anymore. That was the phrase I used: I just can’t do this anymore. And I was probably the worst I’ve ever seen myself in being able to cope with it. It just seemed like it all tumbled down upon my shoulders and I couldn’t see the daylight. It’s like crawling out of a deep hole. I couldn’t do it,” Howe said.
At first, it may seem that it is natural for a person with cancer to be depressed.  Following that line of reasoning, one might think that a physician who diagnosed Bill with depression is making it up, being paternalistic, being judgmental, stigmatizing the poor guy, etc; or that the conceptualization of Bill as a depressed person is due to the reaction that other s have when he can't fulfill his usual responsibilities.  Some may accuse the medical profession of profiteering from what is a purely natural, normal, expected response to a terrible misfortune.  The problem is, those conclusions are not supported by the facts.
Some cancers have a particular effect on emotions: some brain tumors, pancreatic cancer and lung cancer tend to be the most debilitating emotionally. Patients with those types of cancer often have more difficulty with depression and anxiety than patients with other types of cancer. Researchers suspect biochemical factors and the location of the tumor somehow impact the emotions.
If depression in cancer patients were due to the stress of having been diagnosed with a serious illness, then you would expect to see the frequency and severity of the depression correspond with the prognosis of the illness.  Liver cancer, for example, has a high mortality rate, and tends to cause a long and difficult course before death.  But is is not particularly associated with depression.  On the other hand, oncologists have known for a long time that pancreatic cancer has a remarkable propensity to cause depression.  In 1968, the journal Gastroenterology had an article entitled Mental symptoms as an aid in the early diagnosis of carcinoma of the pancreas. (Gastroenterology. 1968 Aug;55(2):191-8)

Of interest in this regard is another article:
Depression in physically ill patients. Don't dismiss it as 'understandable'.
Postgrad Med. 1992 Sep 1;92(3):147-9, 153-4
Rifkin A.
Department of Psychiatry, Albert Einstein College of Medicine, New York.

Depression in the physically ill is common and may even be caused by certain physical disorders (eg, hypothyroidism, pancreatic cancer) or the use of some types of drugs. It should not be dismissed because it is "understandable" in particular situations, but rather, it should be differentiated from overlapping symptoms of the physical disorder and treated. The effect of psychosocial factors should be carefully considered.
More provocative is this:

Are inflammatory cytokines the common link between cancer-associated cachexia and depression?
J Support Oncol. 2005 Jan-Feb;3(1):37-50
Illman J, Corringham R, Robinson D Jr, Davis HM, Rossi JF, Cella D, Trikha M.
Centocor, Inc., Malvern, Pennsylvania, USA.

The prevalence of depression among patients diagnosed with cancer is higher than among the general medical population and is associated with faster tumor progression and shortened survival time. Cancer-related depression often occurs in association with anorexia and cachexia, although until recently the relationship between these conditions has not been well understood. Cachexia is associated with poorer quality of life and survival outcomes and is the eventual cause of death in approximately 30% of all patients with cancer. Recent evidence has linked elevated levels of inflammatory cytokines with both depression and cachexia, and experiments have shown that introducing cytokines induces depression and cachectic symptoms in both humans and rodents, suggesting that there may be a common etiology at the molecular level. Therapeutic agents targeting specific cytokine molecules, such as interleukin-6 or tumor necrosis factor-alpha, are currently being evaluated for their potential to simultaneously treat both depression and cachexia pharmacologically. This review summarizes the available data suggesting a dual role for cytokines in the development of cancer-related depression and cachexia and describes how biologic therapies targeting specific cytokines may improve outcomes beyond depression and cachexia, such as survival and quality of life.
It is clear that there is a physiological basis for major depression, and that there is overlap between the pathophysiology of depression and other illnesses, such as cancer.  But if you get back to the question in the title of this post --What is a disease, anyway? -- it turns out that the answer depends upon your frame of reference.  If you define a disease as a physiological or anatomical derangement that results in impaired function, decreased life expectancy, or decreased quality of life, then mental illness certainly qualifies.  If you define it is a condition in which society accepts that the sick role is appropriate, then the answer gets pretty murky pretty quickly. 

So what about Familial Advanced Sleep Phase Syndrome?  Why did I start this post talking about FASPS, then get into the semantics of diagnosis?  Because it illustrates an important point, that's why.  FASPS is a condition in which there is a known genetic abnormality, with known physiological consequences, that has the potential to interfere with function, and the potential to lower a person's quality of life.  But both of those factors are dependent upon a person's social environment.  Thus, the condition itself is not sufficient to cause a disease state; rather, a disease state results from the interaction between the physiological consequences of the genetic abnormality, and the patient's social environment! 

What this demonstrates is that the concept of disease must include an appreciation for the entire organism, its social milieu, and other aspects of its environment.  For a person with FASPS who wants to be a nurse, or a factory worker, it is no problem if they find a job where they can start work at 6 AM.  For a psychotherapist in private practice, though, it often is essential to be able to offer evening hours.  FASPS would make that impossible.  So the exact same genetic anomaly would cause a disease state in the latter, but not the former. 

Does this concept apply to mental illness?  Certainly not, in the case of schizophrenia.  Such patients have readily demonstrable abnormalities in brain function, as well as decreased life expectancy.  But what about attention deficit hyperactivity disorder?  It is a problem only in a society that has schools and jobs.  For nomadic or hunter-gatherer folks, it would not be a problem.  Does this mean that ADHD is a "manufactured madness," according to Szasz? 

That is a matter of opinion, I suppose, although my opinion is that Szasz is wrong, even in the case of ADHD.  Organisms do not always get to choose their environment.  As Mark Twain said, "Don't go around saying the world owes you a living; the world owes you nothing; it was here first."  However, I would not dismiss totally what Szasz had to say.  Although I don't buy his premise that mental illness is manufactured, I would agree that the stigma is manufactured; I would add that the medical profession has played a role in this, and bears some responsibility for fixing it. 

A person with FASPS might be loved by his or her family, although they may think the patient is a little idiosyncratic; in contrast, the patient's boss might be terribly upset by the patient who comes in late a few times a week.  The boss may think the patient lazy, unmotivated, and/or disloyal.  So while the illness is not manufactured by society, the stigma is.

Another point that might be worth pointing out, at this point, is that is some cases there is no objective test that can can be applied to diagnose an illness, even in cases where there is an identified, testable physiological basis.  Because of the fact that the presence or absence of a disease state depends, in some cases, upon the relationship of the patient to his or her environment, and because it is necessary to exercise judgment about the impact of the physiological anomaly upon the patient. 

In many mental illnesses, there are specific criteria that must be met, in order to establish a diagnosis.  Often, one of the criteria is that the condition must cause "clinically significant distress or impairment in social, occupational, or other important areas of functioning."  This is referred to, technically, as a severity criterion.

A good example of this occurs in the course of diagnosing obsessive-compulsive disorder.  There are many persons who have frequent minor obsessions and compulsions, but who have only minor distress, with trivial impact upon function.  These patients may well have detectable anomalies of brain function, but technically, they do not have an illness.  This is analogous to the person with the CKIdelta gene, but who works from 6 AM to 3 PM.  No distress or impairment = no disease.  Thus, the subjective aspect of diagnosis is not restricted to mental illness. 

In conclusion, I would say that thinking clearly about the process of making a diagnosis, and the meaning of that diagnosis, requires that one exercise discipline.  It is necessary to maintain a clear distinction between the evaluation of the pathophysiology of the condition, and the value judgments that one might make about the patient.  It also is necessary to keep in mind the need for a severity criterion.  Another crucial point is that one has to be cautious about making assumptions regarding the cause of the condition in question.  Often, the cause is not known, as in the case of a cancer patient with depression.  Finally, it is necessary to accept the fact that some aspects of the process of diagnosis are necessarily subjective.  It is pointless to insist upon using only objective criteria, as that simply is not possible in some situations.

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