Wednesday, March 31, 2004

An Activist Pediatrician is Opportunistic, Too.

As a Wednesday Special, I am suspending my usual rule against posting ad hominem attacks.

Articles on the Washington Post website become inaccessible after two weeks.  As it happens, the author also posted a complete copy of the article I am writing about, so you can see it here  after the WaPo copy goes underground.  The author, Dr. Lawrence Diller, is an activist pediatrician who has made a fortune selling books that are critical of his colleagues.

Doc Diller
By Lawrence Diller

Wednesday, March 24, 2004; Page A21

The Food and Drug Administration issued an official warning this week on the increased risks of suicidal tendencies when taking antidepressants such as Prozac. The makers of Prozac and of nearly every other major antidepressant used in this country (Paxil, Zoloft, Wellbutrin, Effexor, Celexa, Lexipro) will have to include a new warning on the package label. This action is the culmination of more than 10 years of efforts to bring to light potential dangers of these medications.

The new warning alerts doctors and patients that in the first days and weeks of treatment, side effects such as agitation, panic, irritability, insomnia and severe restlessness may occur, contributing to an overall increase in the risk of suicide. More than a decade ago similar concerns over Prozac were beaten down in U.S. courts by an onslaught of "expert" testimony of industry-sponsored researchers and legal arrangements that gagged victims and their families with large monetary settlements.

[...] It seems that only the trial lawyers have a vested economic interest in following up on medications. That's a costly post-marketing surveillance system, both to the society that absorbs the legal costs and to the people hurt by a medication, before enough publicity or economic pain is felt by the manufacturer to change the label or withdraw the drug. Nearly 80 percent of respondents to a poll on my Web site said they'd pay at least a 1 percent surcharge on their medications to fund independent, systematic follow-up on pharmaceuticals.

The FDA decision to issue its warning on antidepressants is a vindication, albeit a much delayed "bitter pill" to the families that lost a child to suicide as a result of taking what might have been no better than placebo treatment. How many more children must die from other questionable drugs before our government takes the necessary actions to "heal" the sick regulation of the pharmaceutical industry?  

Go ahead and read the whole thing, if you want, but there is not much point; you get the picture from the first two and last two paragraphs.  Of greater interest is the comparison between Doc Diller's article and one recently published on Reason online. 

Jacob SullumWhy is the FDA scaring people about antidepressants?

The pediatrician Lawrence Diller, writing in The Washington Post, says  the Food and Drug Administration has issued "an official warning...on the increased risks of suicidal tendencies when taking antidepressants such as Prozac." This is probably how most Americans interpreted the FDA's recent public health advisory covering 10 antidepressants.

Yet the FDA emphasizes  it "has not concluded that these drugs cause worsening depression or suicide." Despite more than a decade of publicity about the alleged suicide-triggering properties of Prozac and its cousins, the FDA says, "a causal role for antidepressants in inducing such behaviors has not been established."

It is therefore hard to understand why the FDA is requiring that manufacturers of these drugs add a conspicuous suicide warning to their labels. The warning advises health care providers to "carefully monitor patients receiving antidepressants for possible worsening of depression or suicidality, especially at the beginning of therapy or when the dose either increases or decreases." It says "health providers should be aware that worsening of symptoms could be due to the underlying disease or might be the result of drug therapy."

The FDA defends the warning by arguing that it makes sense to keep an eye on depressed patients even if there's no truth to the claim that antidepressants make people kill themselves. "We think this is good advice whether the drugs did it or not," an FDA official told  The New York Times, "If someone commits suicide, it doesn't really matter whether it's the drug or the underlying disease. In either case, you need to pay attention."

Putting aside the issue of whether people who feel happier after taking antidepressants are suffering from an "underlying disease," this rationale is rather strange. By the same logic, the FDA could require a warning that a heart drug might raise the risk of myocardial infarction not because there was good evidence that it did but because people with heart disease should be closely monitored.

[...] This distinction does not really follow from a concern about suicide. Severely depressed patients are especially likely to kill themselves, meaning that not only the benefits but also the risks (if any) of taking antidepressants are higher for them. Conversely, mildly depressed people may enjoy less dramatic benefits, but any suicide risk also would be lower. It seems the controversy over antidepressants and suicide has become a cover for other, unarticulated concerns about the appropriate use of chemicals to tweak one's mood and personality.

Mr. Sullum has a good point in the concluding sentence.  Unfortunately, he does not provide any evidence to back up his allegation that the "controversy over antidepressants and suicide has become a cover for other, unarticulated concerns about the appropriate use of chemicals to tweak one's mood and personality." 

It probably is not possible to prove such a claim.  After all, who really can know the motivations of another person?  As it happens, we do have some ancillary information that suggests Mr. Sullum is correct in his allegation.  I would add another allegation: that Doc Diller is not only an activist, he is an opportunistic activist who is making a ton of money by ignoring the scientific principles of medical practice, pandering to a market of other anti-psychiatry activists and unwary parents. 

I personally don't care if other anti-psychiatry activists waste their money on his books.  But I do object to him feeding on the fears of parents and fanning the flames of litigation. 

I hasten to add that I cannot prove that he is doing these things.  This is my opinion.  But there are some facts to support these allegations.   I hasten to add also that Mr. Sullum is hardly beyond reproach.  He is the author of Saying Yes: In Defense of Drug Use.  So he has a financial pony in this race, too. 

I suppose if there were ever any hope of me making money off this blog, I could face the same accusations.  But I assume most of my readers know the chances of that.

Back to the point.  What is the evidence that Doc Diller is trying to make a buck, in a way that is unscrupulous?  I did not quote the entire Sullum article, but in it, he points out that the "FDA's decisions are not supposed to be based on anecdotes, which are emotionally compelling but scientifically unreliable."  This is one of the most fundamental principles of medical science.  The literature is full of case reports of one or two patients who exhibited some unexpected drug response.  These reports are posted just in case some kind of pattern emerges.  Then, someone can justify doing a formal study to prove the point.

For example, I recall seeing, about ten years ago, a report about two patients with schizophrenia who got better after being given Pepcid for gastroesophageal reflux.  Pepcid is an H2 blocker that does not cross the blood-brain barrier very well.  So it was not expected to have any effect on the brain, much less having a salutary effect on schizophrenia.  Did anything ever come of it? No.  Just two anecdotal reports that are lost in the dustbin of letters to the editor in some obscure journal. 

Another example: The premarketing studies of the antidepressant Remeron included three cases of neutropenia (low white blood cell count).  This was dutifully reported in the package insert.  The statistical analysis indicated that it was as likely as not to be a fluke.  Was it? Yes.  After the drug had been given to millions of people, no additional cases emerged. 

It is important to recognize that this kind of thing happens all the time.  If you do 20 independent lab tests on a patient, there is a 50% chance that one of them will be abnormal, even if there is nothing wrong with the patient.  Part of the practice of medicine is learning to suspend judgment, to not draw any conclusions, based upon isolated observations.   Surely Doc Diller knows this.  Yet, look at what he has posted on his website:

I've been a doctor for twenty-seven years and thought I was pretty accustomed to the sad and difficult stories I heard about kids in my practice of behavioral pediatrics. Still I wasn't prepared for the tales of devastation and woe as I listened to parents and children speak earlier this week at the Food and Drug Administration meeting on the adverse effects of the anti-depressant drugs on children.
This is ridiculous.  I spent six months in training, in a children's hospital, and I'm sure he has a lot more experience in pediatrics than I do.  He has had to tell parents that their kid has cancer, or cystic fibrosis, or any of a number of awful things, hundreds of times.  He has seen all kinds of "devastation and woe".  It is his job to be able to withstand that with complete æquanimitas.  He goes on:

The problem facing the FDA, though, is that many of these extreme acts could have been the product of the disorders these drugs were meant to treat. Yet only two parents of about forty personal witnesses spoke of the value of the medications. They also happen to be representatives of the National Alliance for the Mentally Ill (NAMI) which has close ties to the psychiatric establishment and drug industry.

I personally know several members of NAMI.  The ones I know are among the kindest, most altruistic people on this planet.  Yes, they do get grants from pharmaceutical companies.  Although I cannot speak for the two parents that Doc Diller saw at the meeting, the NAMI members I know are serious advocates for patients, usually because they have family members who are afflicted with mental illness.  To cast doubt upon their credibility because NAMI accepts corporate contributions is irresponsible.  NAMI has a high rating  among charitable organizations, and they publish openly their financial resources.  See their 2003 annual report  (162 KB PDF) for details.  Notice that many of their large donors are insurance companies.  Insurance companies have an interest in keeping costs low, so they tend to have an agenda opposite that of the pharmaceutical companies.  Other large contributors to NAMI are philanthropic organizations, and there are many individuals and estates that make contributions.  If he means to imply that NAMI is a shill for Big Pharma, he needs to find some actual evidence.

Now look at some excerpts from his presentation  to the President's Council on Bioethics:

Just again, like all psychiatric diagnoses, there are no biological or psychological tests for ADHD, and more interesting to me is looking at the use of stimulants in America, and in the wide variation which points -- you don't know how many people have ADHD for sure, but you can be much more certain of who is using Ritalin, and we will find out in a short time why.

No tests?  This is a summary of tests accepted as evidence by Purdue University  when a student requests accommodations on the basis of ADHD:

The basic diagnostic instrument is the clinical interview. Commonly several other diagnostic instruments are used to provide a broader foundation of information upon which to base a diagnosis and to identify the student's functional status. The following information is provided for the purpose of reference for professionals using other assessment instruments.

The common functional areas and the frequently used diagnostic instruments for each are:

  • Cognitive Functioning – provides a wealth of information on how the student copes with a variety of verbal and visual/spatial tasks. Using one instrument: Wechsler Adult Intelligence Scale-III (WAIS-III) all subtests (as appropriate); or Woodcock Johnson Tests of Cognitive Ability-III.
  • Alternating and Divided Attention – provides information about mental flexibility (the ability to shift focus) and the ability to simultaneously attend to multiple demands. Using at least two instruments: Wisconsin Card Sort; Attentional Capacity Test (ACT); Paced Auditory Serial Addition Test (PASAT); Trail Making Tests, Parts A and B; or Kagen Matching Familiar Figure Test (KMFFT)
  • Target Focused –provides information about sustained and selective attention over time. Using one instrument: Tests of Variable Attention (TOVA); Connors’ Continuous Performance Test (CPT); or Gordon Diagnostic System (GDS).
  • Executive Functioning– provides information about problem solving methods, frustration levels, restlessness, and distractibility. Using at least two instruments: Halstead – Reitan Category Test; Porteus Maze Test; Tower of London (sequencing and planning); Stroop Neurological Screening Test (SNST); Wisconsin Card Sort; Rey-Osterrieth Complex Figure Task; or Letter Cancellation Task.
  • Memory Functioning– provides information about long term and short term memory. Using one instrument. Wechsler Memory Scale- III (WMS-III); California Verbal Learning Test (CVLT); or the Verbal and Nonverbal Selective Reminding Tests.
  • Self and Other Reports – provides information about functioning from questionnaires. Using two instruments (one from a significant other [parent or sibling completing the checklists as it pertains to the student] and the other from the student): Wender Utah Rating Scale (WURS); Barkley Self-Rating Symptom Checklist for ADHD Adults; Copeland System Checklist for Adult Attention Deficit Disorders; Connors’ Adult ADHD Rating Scales (CAARS); or Brown ADD Scales (Adult).
It is true that there is no single test that is conclusively diagnostic of ADHD.  A trained, experienced psychologist has to do a battery of tests, conduct an interview, etc., but to say there are no tests is just plain wrong. 

How good of a grasp of science does Doc Diller have?  See this excerpt from one of my earlier posts; this is also from the December 12, 2002 presentation to the PCBE:

 [...]it is a special pleasure and privilege to welcome Dr. Lawrence Diller to the council this afternoon. In an area in which there have been zealots and radicals on all sides, this is a man who has occupied the sober middle voice of moderation, and of care, and of proper concern.

Dr. Diller has occupied the sober middle, a good place for someone talking about a controlled substance.  The man in the sober middle has this to say about the mechanism of action of methylphenidate:

Now, a little bit on the drugs themselves. The way that these stimulants work, is that they block dopamine receptor sites, and therefore increase the neurotransmitter at the synapse, and tagged dopamine seems to show up more at the pre-frontal cortex and the local cerruleus [sic] in the brain.

Now, compare this with the following text from Psychiatric News September 21, 2001 Volume 36 Number 18 p. 18:  (The Psychiatric News article is a summary of the findings reported originally in The Journal of Neuroscience, 2001, 21:RC121:1-5.)

[...]Although methylphenidate has been prescribed for nearly 50 years, its mechanisms of action have been understood only poorly. A central nervous system stimulant, the drug is believed to block both the dopamine and norepinephrine transporters responsible for clearing the neurotransmitters out of the synapse after a signal has been transmitted from one neuron to the next, in the same way that an SSRI blocks the reuptake of serotonin.

PET scan images, taken at the level of the striatum (left) and the cerebellum (right) of a radiotracer specific to dopamine D2 receptors, show reduced binding of the tracer in the striatum after administration of 60 mg of oral methylphenidate (bottom) compared with placebo (top).[...]

Notice two things: 1) The mechanism of action of methylphenidate involves blockade of the dopamine reuptake transporters, not the dopamine receptors, and 2) The increased dopamine shows up in the striatum, not the prefrontal cortex.  (The dopamine displaces the radioactive tracer from the receptors, so the treated patients show less radioactivity where there is more dopamine released.) 

Dr. Diller may be sober, he may not be a zealot or a radical, but in his work helping to refine science policy for the President of the United States, he made two factual errors in one sentence. 

Turning to his WaPo Opinion article, the last sentence of his opening paragraph is: "This [FDA announcement] action is the culmination of more than 10 years of efforts to bring to light potential dangers of these medications."

When I was in medical school, I was taught that it is important to monitor patients for suicide risk shortly after starting an antidepressant.  That would have been in the early- to mid- 1980's.  None of the medications mentioned in the FDA announcement had even been put on the market yet.  The fact is, the risk he is talking about is not news.  It just isn't.  The fact that the FDA has issued a warning is news, but it does not represent new scientific knowledge.  There are two points about this: First, the FDA is a government organization that serves a regulatory function.  It is not fundamentally a scientific institution.  Second, the FDA issues warnings almost every day.  For example, they issued 37 medication warnings in February 2004.  (If you want, you can sign up for  e-mail alerts of these warnings.)  We cannot know for sure what motivated Doc Diller to write about this one particular warning, but looking at his website, it is apparent that he has a particular interest in bashing psychotropic medication. 

Further on in his Opinion article, he states. "It seems that only the trial lawyers have a vested economic interest in following up on medications."  If this is true, why is it that the FDA issues such frequent warnings?  Are we to believe that trial lawyers instigated all these warnings?  No, the fact is, the FDA and the pharmaceutical industry are paying close attention to safety issues.  Usually, they act on these issues when it appears to be appropriate.  Yes, there have been some significant failures in the system, including some unconscionable cover-ups.  But even Doc Diller has not established a case for the contention that there has been a cover-up of the possible link between antidepressants and suicide. 

Dr. Diller wrote his Opinion piece and got it published in the Washington Post.  I am sure this has attracted some attention to him, and his books, and his website; no doubt, he continues to profit from this.  If only he would spend more time studying the science of medicine, he might be able to write something that actually is accurate and newsworthy.