Do not think about, write about or deal with human behavior without determining the effects of incentives.
Merry Christmas
A Learning Exercise for ADHD
Thursday, December 23, 2010
The impetus for this posting is a recent series of articles in the New York Times on ADHD. The main article was written by Perri Klass. The Times article takes the stance that rambunctious children have a biological deficit resulting from faulty genetics and that they need medication. Furthermore, her take on this is that every neuroscientist in the world knows that ADHD is a disease. For Klass, there is simply no debate about this, and she implies that anyone who thinks so is “out there”.
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Why does the debate over fixing ADHD with medication smell like the debate over Global Warming? Those who don’t believe are marginal and stupid.
We have noticed over the years that that these types of newspaper articles are very formulaic. You could replace “ADHD” with many other psychiatric disorders and clearly, this is a story we have read before. Furthermore, very similar versions of this type of article appeared twenty years ago, and they will surely be around twenty years from now. The formula goes as follows: “XYZ Condition” is a biologically- based brain disease; some big shot brain expert is quoted saying it is, and the reporter writes that brain imaging has shown pathology; twin studies show it is genetic, a gene has just been discovered (or is right around the corner). The articles ignores the failure to replicate every previous gene study ,ignores all the problems with the studies being cited, and highlights the fact that once the presumed gene is discovered, we will have a cure, etc. Needless to say the formula is getting old. The frustrating part with all this is that you would think the New York Times would have figured this out by now.
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Our proposed questions:
Prevalence
1) What worries many neuroscientists about how the general public misunderstands ADHD and other psychiatric disorders? While many advertisements and the lay media state that ADHD and other psychiatric disorders have been shown to result from a proven biological deficit, has this ever been shown to be the case? Is this emphasis on unproven theories possibly one reason for the meteoric rise in the use of psychotropic drug use in children? Hint: In the same articles and advertisements which state that these diseases have a biological basis, pay close attention to the actual scientific studies they cite.
2) In 1995, a report in Archives of General Psychiatry stated, “Cocaine, which is one of the most reinforcing and addictive of the abused drugs, has pharmacological actions that are very similar to those of methylphenidate (Ritalin) which is the most commonly prescribed psychotropic medication for children in the US.” From DeGrandpre, The Cult of Psychopharmacology.
3) If we are diagnosing children as young as three with ADHD does this suggest a problem with how we view childhood? In Florida it has been reported that upwards of 80% of the foster home population are diagnosed with ADHD or another psychiatric disorder. Does this suggest that these children’s problems are caused by a biological deficit or a problematic environment? Many of these children, some under three-years of age, have been prescribed antipsychotics. Do you think that legislators should be worried about this? Do you think that we as a society should be worried about this? If this is a problem, who is responsible for this?
4) Stimulants have been shown to increase attention span for anyone. As an example, take two college students who take stimulants because they want to get better grades. One student gets his medication from a doctor and one gets it from a friend? Is there a difference between these two students? What is that difference?
5) Is it inappropriate to use Ritalin to increase academic performance? Is it inappropriate to use steroids to increase athletic performance?
6) Why does the United States consume 85% of the world’s ADHD medication?
7) If stimulants are nothing but a performance enhancing drug why not just call it that, instead of talking about a disease? Allen Frances the primary author of DSM-IV, stated recently, “Especially in adolescents and adults, real or perceived attention problems are so common and so nonspecific that ADHD can be easily overdiagnosed in those suffering from any number of other mental disorders and in those who are merely seeking performance enhancement.”
Genetics
1) Just because a trait is shown to be genetic does that mean that the trait is a disease? For instance, some people have blond hair and some have brown hair? Does one of these groups have a disease? Some people are shier than others? Is shyness a disease?
2) Every trait falls on a spectrum- Where do we draw the line with activity levels? Do we say that five percent, ten percent, or twenty percent have a disease? Can we use “science” to answer this question or does it come down to what is considered acceptable by a certain population? The prevalence of ADHD varies from state to state, from country to country, and from one doctor’s office to another? If 15% of boys in a certain age group have this condition, should it be thought of as a disease or normal human variation?
3) Heritability is a term often used in selective breeding programs. How is heritability determined? Is it the same thing as the concordance rate of Identical twins?
4) If a trait is more common in identical twins than non-identical twins does that automatically mean that the trait is genetic? What else might account for a higher concordance in identical compared to non-identical twins? What if identical twins have more similar environments than non-identical twins?
5) In the 2002 consensus statement, which Klass mentions in her editorial, the authors mentioned that twin studies were said to have provided evidence that ADHD is a real medical condition,” and the authors even went on to claim that one (unnamed) gene has recently been reliably demonstrated to be associated with the disorder and that the search is underway by more than 12 different scientific teams worldwide at this time. Has this search proven fruitful?
6) Considering that the psychiatry profession has a long history of announcing the discovery of genes for various conditions, only to find that the studies could not be replicated, is it wise to base one’s entire argument about ADHD being a disease on a study that, if history is correct, will probably not stand the test of time?
7) If it is really true that genetics accounts for 80% of variation then why haven’t these genes been discovered yet? Scientists have certainly searched for them. Is it possible that the 80% is a gross overestimation? As a primer on the problems with genetic research one might want to look at The Great DNA Deficit: Are Genes for Disease a Mirage by Jonathan Latham and Allison Wilson
Neuroimaging
1) In the usually mentioned neuroimaging studies, the researchers often compare ADHD brains to controls. The idea being that any difference between normals and ADDH brains is indicative of pathology, however in many cases the ADHD brains have been exposed to medications. In a study like this how do we know if the medications caused the damage or if it is an organic pathology?
2) Compare these two studies. Both had access to medication naïve children. Yet one reported on the difference and one did not. 1) In this NIMH sponsored study the authors had access to medication naïve children and reported that the medication did not cause brain changes. Note that there was large age difference between controls and medicated children. 2) Here is another NIMH sponsored study that within the ADHD group had non-medicated and medicated children but the authors have never released the data on the comparison between the medicated and unmedicated children? Even a Freedom of Information act request to see the data was denied. Why do you think these authors never published this comparison?
3) Do you think there is a possibility of long-term stimulant use causing neuronal damage? For instance is there a possibility that someone who is on stimulants from age 2 through 20 might show brain damage? What about the fact that numerous children are being given atypical antipsychotics. Do you think this might cause long-term brain damage?
4) Consider the following example provided by Robert Whitaker in his book, Anatomy of an Epidemic, of how the ADHD marketing message is often presented.
“…there were a couple of instances when psychiatrists were forced to say something to reporters about one of the studies, and each time they spun the results. For example, when the NIMH announced the three-year results from its MTA study of ADHD treatments, it did not inform the public that stimulant usage during the third year was a “marker of deterioration.” Instead it put out a press release with this headline: IMPROVEMENT FOLLOWING ADHD TREATMENT SUSTAINED FOR MOST CHILDREN.” (pages. 310-311).
Does this seem like spin to you? What other important messages about ADHD might have been spun?
5) If, as some researchers have suggested, ADHD children have brains which are slightly slower to mature, should this really be called a “disease?” Should we medicate them just so their brains can catch up?
6) If scientists have shown that imaging studies have discovered an anatomic lesion in the brains of ADHD children, why are imaging tests not used to diagnose ADHD?
Chemical Imbalance
1) Klass mentions that there is an imbalance of dopamine in the brains of ADHD children? Have scientists proved this?
2) Consider this from DeGrandpre, commenting on the work of Norma Volkow, “Ritalin could be substituted for cocaine in addiction research. Ritalin is like cocaine in that it increases synaptic dopamine by inhibiting dopamine reuptake, it has equivalent reinforcing effects to those of cocaine, and its intravenous administration induces a high similar to that of cocaine.” (page 7)
The Media
1) Do you think that The Times reporter and the author of the Op-Ed piece are aware of these more complex issues? Or that they just choose to ignore them?
2) In her first paragraph, Klass mentions the published statement that by a group of concerned scientists and clinicians that not everyone thinks ADHD is a disease, but she ignores that another group of neuroscientists also took the other side and that their paper was published in the same journal. Do you consider this good reporting?
In The New Republic, psychiatrist Sally Satel recently reviewed Carl Elliott’s new Book, White Coat, Black Hat: Adventures on the Dark Side. Satel and Elliot have entirely different views about the complex relationship between clinicians and the pharmaceutical industry and the forces at work on the decision making process that clinicians go through when deciding on the best treatment for their patients. Like many others, Elliott is concerned about the problematic role that money is playing in what should be scientific based decisions. Satel, a fellow at the American Enterprise Institute, does not see a problem with the relationship and provides a less than flattering review of Elliott’s book. However, following the law of unintended consequences, Satel’s review presents somewhat of a problem for academic medicine, because instead of successfully knocking down his book, she has essentially provided even more evidence to support Carl Elliot’s thesis – that clinical decisions are not strictly based on evidence. Satel seems to ignore all the countless newspaper articles, magazine exposes, lawsuits, and editorials from the leading medical journals, all of which have revealed the growing problem of commercial influence within the medical literature.
When it comes to the problematic relationship between doctors and pharmaceutical companies, there are two areas of concern. If you have ever been a patient, you are probably fully aware of the first problem – the ever present freebies and other trinkets, such as pens, clocks, and tape dispensers that are in many doctor’s offices. Satel is correct that there has been a noticeable effort by everyone involved to move away from this practice, however the free trinkets are not the major problem. To think that this is the major problem is to miss the forest through the trees. There are probably very few physicians who prescribe drugs because they want a new coffee cup.
Certainly most physicians, including Satel, prescribe a certain medication because they believe it is safe and effective- often because they are persuaded by a peer-reviewed journal article. All the better if they read the article in a top tier journal like the New England Journal of Medicine, or the Journal of the American Medical Association, authored by a professor from Harvard, Princeton, or Yale. Satel states: “It is one thing to scorn emblazoned mouse pads and other tchotchkes, but quite another to denounce academic-industry relationships.” In other words, she has it totally backwards. What Satel apparently does not understand, but which Elliott documents clearly in his book, is that the peer-reviewed literature is the real problem – the idea of the sacrosanct “peer-reviewed literature” is quickly becoming more myth than reality. Prozac and the other antidepressants didn’t become a household name because clinicians thought that the coffee mugs were neat; the antidepressants became household names because the medical literature said they were efficacious and that the side-effects were minimal. However, we now know that the antidepressants do not work very well in the short term, at least according to the clinical trial literature, and that long-term use of antidepressants appears to have problematic outcomes.
Given all that has been published over the past several years about the problems with the medical literature- such as ghostwriting and selective reporting of study results- only a very naïve clinician could really believe that the peer reviewed clinical trial literature is an accurate reflection of the true evidence base about a drug. Indeed, medical journal editors are increasingly skeptical, the FDA is skeptical, and medical school deans are skeptical, yet Satel is not?
You could pick virtually any recent blockbuster drug to illustrate the point that the medical literature is biased, but since they have been in the news lately let’s take the atypical antipsychotics. When Risperdal was coming on the market in 1992 the FDA told Johnson and Johnson that “We would consider any advertisement or promotion labeling for RISPERDAL false, misleading or lacking fair balance under section 502 of the Act if there is a presentation of data that conveys the impression that Risperidone is superior to haloperidol or any other marketed antipsychotic drug product with regard to safety or effectiveness.” Yet this drug, which according to the FDA, was no better than the older drugs, and cost 30 times more, went on to become Johnson and Johnson’s 4th most profitable drug in 2004. But if the companies couldn’t advertise it as better and safer how did it achieve this success?
Risperdal became a blockbuster because the companies could hire prominent physicians and scientists to say the newer generation drugs were better (even though it would be illegal for the company to run an advertisement making this claim). At company talks, clinicians would hear Key Opinions Leaders (KOLs) tout the drug, and they could read academic articles, supposedly authored by KOLs but often really written by company employees, saying that the newer drugs were better. Such experts certainly should have known the biased and flawed nature of the evidence that they were citing to support the superiority of the new drugs. And now, somewhat unsurprisingly, a decade later, through various government funded studies, we now know that the atypicals have not lived up to the companies’ claims. When the results came out, Robert Rosenheck, one of the researchers, said: “What you have is both industry and opinion leaders claiming this is a breakthrough drug. And then three large government-funded studies come out, and none of them finds evidence of a breakthrough.”
We are now at a point where multiple State Attorneys General are suing antipsychotic manufacturers, claiming that the states were misled into paying for medications that cost more but were no better than the cheaper ones. Johnson and Johnson just lost a $257.7 million jury verdict over misleading claims about the safety of Risperdal, and the other atypicals are involved in similar suits because of misleading marketing practices. And to top it off, in spite of the fact that it is hard to find defenders of the practice, the medical community is now prescribing the atypicals to the two most vulnerable populations: children under five, and the elderly. Ironically, Satel mentions that we need to punish and police the wrong doers. This brings up an uncomfortable question for academics in psychiatry: Rather than suing the pharmaceutical companies, shouldn’t the Attorneys General sue the academics who the companies hired to say exactly what the FDA forbid the companies from saying?
Although Satel insists that academic-industry relations are not a problem, ghostwriting, perhaps the most egregious practice of all takes place at the nexus of industry and the academy. Take Study 329, a clinical trial of paroxetine for pediatric depression. The study failed to find a positive effect on any of eight protocol-defined outcome measures but the resulting publication selectively reported that paroxetine was “generally well tolerated and effective for major depression in adolescents.” The author list included the biggest names in child psychiatry, yet it’s now known that the true author was a ghostwriter. (This came out in court proceedings; we have no idea how many other studies published in the last 15 years were also ghostwritten). When critics pointed out the problems with the study to the editor of the journal, she published an angry reply denouncing the critics – if she only knew what was coming. The study she defended has gone on to become the quintessential example of the corruption of the medical literature and academic medicine, as subsequent internal company documents were eventually published showing that the company knew that the study was negative, but they were still able to find professors to put their name on a paper which said the findings were positive. David Healy has said that the research into the use of SSRIs and childhood depression represents possibly the greatest divide in all of medicine when one compares the published studies to the unpublished data.
Unfortunately, the marketing of SSRIs within medical journals is not unique. No one knows the true extent of ghostwriting but some have suggested that virtually all the clinical trial literature has been ghostwritten. Ghostwriting is not something that happened every now and then with just a few drugs. As the table attached to this blog posting shows, almost all the blockbuster medications that have been embroiled in lawsuits and fines have had marketing plans which utilized the services of ghostwriters.
Satel also suggests the need for studies to look at prescribing habits before jumping to conclusions: “Only prospective data on the prescribing habits and rationales of real physicians in real medical settings will answer the question.” But we already have loads of data on the fact that numerous prescriptions for numerous medications have been prescribed for millions of people with little scientific rationale. Pick your drug. Vioxx was prescribed unnecessarily to millions of people, expensive blood pressure medications continue to be prescribed even though in many cases cheaper diuretics work just as well, the atypicals are prescribed to children under three, Lexapro is prescribed for depression when the only significant difference between it and Celexa is that it costs more.
Satel also says that all of this in the past. In her words, “The wild-west days of free ranging-drug salesman, unfortunately keeps alive the impression that corruption, both subtle and overt, is rife.” Elliot’s book does document many instances of obvious (or likely) corruption; for instance, a surgeon who recently testified in front of Congress regarding proper treatment for injured soldiers who was secretly a paid lobbyist for a medical devices company; the death of Jessie Gelsinger in a clinical trial of gene therapy; and again, the fact that peer-reviewed medical journal articles are routinely ghost-authored by pharmaceutical companies. To most, these examples (among many others that could be cited) would seem to obviously point to the fact that corruption is still a problem, but Satel misses the big picture. While most of the general public can’t even comprehend the idea that professors have their articles written by company employees, very few Universities have placed into effect policies that control ghostwriting. And, professors who are known to have been involved in ghostwriting are not scorned for working for pharmaceutical companies in the pages of medical journals to the detriment of evidence-based medicine. Furthermore, several major psychiatry departments in major medical schools are led by chairpersons with a history of being involved in ghostwriting. The author list for Study 329 included professors from numerous institutions. Satel says that one solution is for junior faculty to only meet with pharmaceutical reps in the presence of senior faculty members. But where is the evidence that the senior faculty are more adept at critically thinking about conflicts-of-interest? In fact, the KOLs come from the ranks of senior faculty members, not the junior members.
One area that we agree with Satel about is the misguided idea that just because someone has a conflict of interest that they are automatically presumed to be wrong. But, just because someone has a conflict of interest does not mean that what they say about a medication is tainted. Someone with a large conflict could certainly be correct. However, there is a flip side to this belief, and quite possibly one reason that the general public is skeptical. Namely, that when someone is found to be making false statements, or selectively reports favorable data, and subsequently it is determined that they have an undisclosed conflict, surely people will speculate that money is the source of the problem. Surely this is not the case all the time, but if there were not so many examples of this, then possibly the medical editors, medical school deans, and the general public would not be so skeptical.
Sally Satel’s view of academics and companies working together for the betterment of the patients is a noble one but, when one thoughtfully considers what has gone on during the last ten years, as Elliott has done, it is unfortunately not a realistic view of how academic medicine is functioning. And, even more unfortunately, it will be difficult to solve the problems at the industry-academia interface as long as some are whistling past the graveyard, insisting that the problems do not exist in the first place.
Jeffrey Lacasse, Ph.D.
Assistant Professor of Social Work at Arizona State University in Phoenix, Arizona. He has published research on barriers to evidence-based mental health practice, including articles on critical thinking in mental health, clinical treatment of children, and psychiatric medications.
Jonathan Leo, Ph.D.
Professor of Neuroanatomy at Lincoln Memorial University-DeBusk College of Osteopathic Medicine. His research examines the biological basis of mental disorders such as ADHD, schizophrenia, and clinical depression. Rethinking ADHD: From Brain to Culture, a co-edited volume with psychiatrist Sami Timimi, was released by Palgrave Macmillan in 2009.
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The chemical imbalance which is always found but never demonstrated. This nonsense will end when someone is disciplined by the courts, an unwieldy, slow and coarse instrument if ever there was one, but which will inevitably occur.
Cheerio and ttfn,
Grant Coulson
Cui Bono–Cherchez les Contingencies
