British Psychiatrists Criticize Rise Of Bipolar Disorder In Adults, Children

David Healy and his colleague Joanna Le Noury have a new paper out, which examines the rise of bipolar disorder in both adults and children and puts it all in some kind of historical context. It's a lengthier examination of what Healy calls disease mongering than his PLoS paper of 2006. If you want to avoid my summary of this new piece, which I think is a withering attack on just about everyone in the mental health industry, then read their paper here (it's a .pdf file).

This is a lengthy post, but I think it's worth laying out the authors' key points since they are pushing back against some powerful forces in our culture and, at the end, asking if the bipolar child paradigm isn't a new form of Munchausen’s syndrome. I should also note that this site makes an appearance by inference in the article, which was published in the International Journal of Risk & Safety in Medicine.

BTW, I usually don't pinch this much copy from an article, but this is article is rather significant and worth the departure from my usual practice.

The two psych researchers begin with Depakote:

"Early market research was linked to the introduction of Depakote. In the form of sodium valproate, this anticonvulsant had been available and shown to be helpful in manic-depressive illness from the mid1960s. Abbott Laboratories reformulated it as semi-sodium valproate,2 which it was claimed formed a more stable solution than sodium valproate. This trivial distinction was sufficient to enable the company to gain a patent on the new compound, which as Depakote was introduced in 1995 for the treatment of mania. Depakote was approved by the Food and Drugs Administration on the basis of trials that showed this very sedative agent could produce beneficial effects in acute manic states. Any sedative agent can produce clinical trial benefits in acute manic states but no company had chosen to do this up till then, as manic states were comparatively rare and were adequately controlled by available treatments. Depakote was advertised as a “mood stabilizer”. Had it been advertised as prophylactic for manicdepressive disorder, FDA would have had to rule the advertisement illegal, as a prophylactic effect for valproate had not been demonstrated to the standards required for licensing. The term mood stabilizer in contrast was a term that had no precise clinical or neuroscientific meaning. As such it was not open to legal sanction. It was a new brand."

Healy and Le Noury aren't done.

"But in addition to branding a new class of psychotropic drugs, the 1990s saw the rebranding of an old illness. Manic-depressive illness became bipolar disorder. While the term bipolar disorder had been introduced in DSM-III in 1980, as late as 1990 the leading book on this disease was called ManicDepressive Disease [16]. It is rare to hear the term manic-depressive illness now. This combination of a brand new disease and brand new drug class is historically unprecedented within psychiatry.

"Lilly, Janssen and Astra-Zeneca, the makers of the antipsychotic drugs, olanzapine (Zyprexa), risperidone (Risperdal) and quetiapine (Seroquel), respectively sought indications in this area and the steps they have taken to market their compounds as mood stabilizers illustrate how companies go about making markets."

And, they do. They offer an example of disease mongering by Eli Lilly from a patient leaflet:

“'Bipolar disorder is a life long illness needing life long treatment; that symptoms come and go but the illness stays; that people feel better because the medication is working; that almost everyone who stops taking the medication will get ill again and that the more episodes you have the more difficult they are to treat.'"

I think most of us recognize what a profound exaggeration that is on Lilly's part, as well as on the part of docs who subscribe to the lifetime illness business. The comes the hammer:

"[W]hen all placebo-controlled studies of Depakote, Zyprexa and Risperdal in the prophylaxis of bipolar disorder are combined they show a doubling of the risk of suicidal acts on active treatment compared to placebo. In addition, valproate and other anticonvulsants are among the most teratogenic in medicine. These claims about the benefits of treatment therefore appear misleading. No company could make such public statements without the regulators intervening. But by using patient groups or academics, companies can palm off the legal liability for such claims."

They go after those silly "look at the famous people with bipolar disorder" lists:

"A second aspect of the marketing of the drugs uses celebrities such as writers, poets, playwrights, artists and composers who have supposedly been bipolar. Lists circulate featuring most of the major artists of the 19th and 20th Century intimating they have been bipolar, when in fact very few if any had a diagnosis of manic-depressive illness."

They talk about the mood journals pressed upon patients which litter the Internet, and they briefly discuss, as I have at length, that 'the risks of suicide, alcoholism, divorce, and career failure are marketed.'

And:

"All of the above come together in a fifth strategy in North America – direct to consumer advertising. A now famous advertisement produced by Lilly, the makers of Zyprexa (olanzapine) begins with a vibrant woman dancing late into the night. A background voice says, 'Your doctor never sees you like this.' The advert cuts to a shrunken and glum figure, and the voiceover now says, 'This is who your doctor sees.' Cutting again to the woman, in active shopping mode, clutching bags with the latest brand names, we hear: 'That is why so many people being treated for bipolar disorder are being treated for depression and aren’t getting any better – because depression is only half the story.' We see the woman depressed, looking at bills that have arrived in the post before switching to seeing her again energetically painting her apartment. 'That fast talking, energetic, quick tempered, up-all-night you,' says the voiceover, 'probably never shows up in the doctor’s office.'"

"Viewers are encouraged to log onto bipolarawareness.com, which takes them to a 'Bipolar Help Center,' sponsored by Lilly Pharmaceuticals. This contains a 'mood disorder questionnaire.' In the television advert, we see our heroine logging onto bipolarawareness.com and finding this questionnaire. The voice encourages the viewer to follow her example: 'Take the test you can take to your doctor, it can change your life. Getting a correct diagnosis is the first step in helping your doctor to help you.'"

"No drugs are mentioned. The advert markets bipolar disorder. Whether this is a genuine attempt to alert people who may be suffering from a debilitating disease, or an example of disease mongering, it will reach beyond those suffering from a clearcut mood disorder to others who as a consequence will be more likely to see aspects of their personal experiences in a way that will lead to medical consultations and will shape the outcome of those consultations. 'Mood-watching' like this risks transforming variations from an emotional even keel into indicators of latent or actual bipolar disorder. This advert appeared in 2002 shortly after Zyprexa had received a license for treating mania, when the company was running trials to establish olanzapine as a 'mood stabilizer.'"

As I've reported before, Lilly saw Zyprexa as a new mood stabilizer, the new Lithium, way back in the mid-1990s. I've noted before that Lilly and BMS have both actively targeted women in their advertising and marketing. I don't know of any evidence that either drug is a mood stabilizer, but I know of plenty of evidence showing that using both drugs as if they were is not good for patients.

Then:

"The upshot of this marketing has been to alter dramatically the landscape of mental disorders. Until recently manic depressive illness was a rare disorder in the United States and Canada involving 10 per million new cases per year or 3300 new cases per year. This was a disorder that was 8 times less common than schizophrenia. In contrast bipolar disorder is now marketed as affecting 5% of the United States and Canada – that is 16.5 million North Americans, which would make it is as common as depression and 10 times more common than schizophrenia. Clinicians are being encouraged to detect and treat it. They are educated to suspect that many cases of depression, anxiety or schizophrenia may be bipolar disorder and that treatment should be adjusted accordingly. And, where recently no clinicians would have accepted this disorder began before adolescence, many it seems are now prepared to accept that it can be detected in preschoolers."

And, then, the authors go after the bipolar child paradigm and especially the role of some academics. They trace the early rise of bipolar disorder in the mid-1990s to Washington University researcher Barbara Geller (who I should note has said some of what's going on around bipolar in kids to be excessive) and figures at Harvard (or Mass General) who suddenly began offering "proof" that many ADHD kids in fact had bipolar disorder. Here's what the authors think of their evidence:

"In 1996, a paper from an influential group, based at Massachusetts’ General Hospital, working primarily on ADHD, suggested there were patients who might appear to have ADHD who in fact had mania or bipolar disorder. This study had used lay raters, did not interview the children about themselves, did not use prepubertal age specific mania items, and used an instrument designed for studying the epidemiology of ADHD. Nevertheless the message stuck. Cases of bipolar disorder were being misdiagnosed as ADHD. Given the many children diagnosed with ADHD who do not respond to stimulants, and who are already in the treatment system, this was a potent message for clinicians casting round for some other option."

Lay raters? Didn't interview the kids? That's fascinating. And then the two offer this rebuttal to Americans who complain about the DSM-IV being so rigid that of course kids can't be diagnosed with bipolar disorder:

"Another ambiguity that the framers of the American position fail to advert to is a problem with DSM-IV. Advocates of pediatric bipolar disorder repeatedly point to problems with DSM-IV that hold them back from making diagnoses. But in fact, DSM-IV is more permissive than the rest of world in requiring a diagnosis of bipolar disorder following a manic episode – in practice any sustained episode of overactivity. The International Classification of Disease in contrast allows several manic episodes to be diagnosed without a commitment to the diagnosis of bipolar disorder. The rest of the world believes it simply does not know enough even about the relatively well understood adult illness to achieve diagnostic consistency worldwide. DSM-IV in fact therefore makes it easier to diagnose bipolar disorder than any other classification system, but therapeutic enthusiasts want an even further loosening of these already lax criteria.

"Finally, we appear to have entered a world of operational criteria by proxy. Clinicians making these diagnoses are not making diagnoses based on publicly visible signs in the patients in front of them, or publicly demonstrable on diagnostic tests, as is traditional in medicine. Nor are they making the diagnoses based on what their patients say, as has been standard in adult psychiatry, but rather these are diagnoses made on the basis of what third parties, such as parents or teachers, say without apparently any method to assess the range of influences that might trigger parents or teachers to say such things."

And, then:

"Where one might have thought some of the more distinguished institutions would bring a skeptical note to bear on this, they appear instead to be fueling the fire. Massachusetts’s General Hospital (MGH) have run trials of the antipsychotics risperidone and olanzapine on children with a mean age of 4 years old. A mean age of 4 all but guarantees three and possibly two year olds have been recruited to these studies.

"MGH in fact recruited juvenile subjects for these trials by running its own DTC adverts featuring clinicians and parents alerting parents to the fact that difficult and aggressive behavior in children aged 4 and up might stem from bipolar disorder. Given that it is all but impossible for a short term trial of sedative agents in pediatric states characterized by overactivity not to show some rating scale changes that can be regarded as beneficial, the research can only cement the apparent reality of juvenile bipolar disorder into place.

"As a result where it is still rare for clinicians elsewhere in the world to make the diagnosis of manicdepressive illness before patients reach their mid to late teens, drugs like olanzapine and risperidone are now in extensive and increasing use for children including preschoolers in America with relatively little questioning of this development. Studies run by academics that apparently display some benefits for a compound have possibly become even more attractive to pharmaceutical companies than submitting the data to the FDA in order to seek a license for the treatment of children. Companies can rely on clinicians to follow a lead given by academics speaking on meeting platforms or in published articles. The first satellite symposium on juvenile bipolar disorder at a major mainstream meeting, the American Psychiatric Association meeting in 2003 featured the distinguished clinical faculty of MGH. The symposium was supported by an unrestricted educational grant. None of the speakers will have been asked to say anything other than what they would have said in any event. The power of companies does not lie in dictating what a speaker will say but in providing platforms for particular views. If significant numbers of clinicians in the audience are persuaded by what distinguished experts say, companies may not need to submit data to FDA and risk having lawyers or others pry through their archives to see what the actual results of studies look like. As an additional benefit, academics come a lot cheaper than putting a sales force in the field."

The following will be a controversial assessment on the part of the authors, at least for some who read this:

"If the process outlined here was one that could reasonably be expected to lead to benefits it could regarded as therapeutic. But given that there is no evidence for benefit and abundant prima facie evidence that giving the drugs in question to vulnerable subjects in such quantities cannot but produce consequent difficulties for many of these minors, one has to wonder whether we are not witnessing instead a variation on Munchausen’s syndrome, where some significant other wants the individual to be ill and these significant others derive some gain from these proxy illnesses."

OK, that's quite enough. What do you all think of the article and how Healy and his colleague have made their case?

I should note with a certain amount of pride that the authors note that Lilly saw opportunities for the use of Zyprexa in children back in 1997. The article's footnote (number 39) points to one of the Zyprexa documents, which was obtained from my site, as the source for their assertion.

Posted by Philip Dawdy at December 13, 2007 12:05 AM
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