Wednesday, April 06, 2005

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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