This marketing plan was plainly documented with the unauthorized release of Eli Lilly's own company marketing memos as part of a US Justice Department investigation—the so called Zyprexa Documents. Although highly effective in curbing delusions and hallucinations in psychotic patients, these medicines are potentially toxic and do nothing to solve the interpersonal and psychological problems of many of the mental health patients to whom they are now prescribed.
"Disease mongering" is a term used for marketing techniques designed to accomplish the goals Dr. Frances alluded to in the quote at the top of this post. The ongoing mongering of bipolar disorder by the pharmaceutical companies uses many tricks. Often so-called researchers and practitioners alike do totally inadequate diagnostic evaluations using highly inaccurate and misleading symptom checklists; other doctors employ the completely unvalidated concept of bipolar spectrum, or b.s. as I like to call it.
A highly transparent example of disease-mongering was recently published in a respected psychiatric journal, the Archives of General Psychiatry. Five hundred twenty-one hospital-based or community psychiatrists in 18 countries in Asia, Europe, and Africa between April 1, 2008, and April 30, 2009 were involved in a “research” project which was designed primaily to shape their thinking and diagnosing, and altering diagnostic paradigms in those countries.
The article is titled Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode and was “designed, conducted and prepared” by Sanofi-Aventis. Sanofi-Aventis markets an atypical antipsychotic named Solian, which is the brand name of the drug amisulpride. (Not FDA-approved in the United States).
The supposed "results" of the study:
“These results are from a large, three-continent, culturally generalizable study conducted by practicing psychiatrists. The data indicate that, whereas with application of the DSM-IV-TR criteria, 16.1 percent of patients with Major Depressive Episodes met criteria for either bipolar I or bipolar II disorder, this rate rose to 47 percent with application of the bipolarity-specifier criteria.
These results suggest that bipolar features are more frequent in patients with MDE than indicated by DSM-IV-TR criteria. Almost half of the entire 5098 cohort presented the core symptoms of bipolarity (elevated mood, irritable mood, or increased activity), and these symptoms led to unequivocal changes in behavior that were observable by others in a similar proportion of patients.”
What this means is that, if this were true, half of patients who exhibit Major Depressive Episodes might actually bipolar and should be taking “mood stabilizers.” Not lithium, I suppose, but the aforementioned atypical antipsychotics.
The article goes on to make this point by stating: “Major depressive disorder, the most common psychiatric illness, is often chronic and a major cause of disability. Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers.”
All of the "researchers" recruited received fees, on a per patient basis, from Sanofi-Aventis in recognition of their participation in the study. The key lead authors all have significant Pharma connections.
So what's wrong with the study? Well, that hinges on the meaning of the term "bipolarity specifier" that was added to the usual, DSM criteria for bipolar disorder. This assumes that this additional test has been validated as being predictive of actual bipolar disorder, which is a "fact" not in evidence. It sounds in the study description as if this were an established and valid measure.
Here's the defintion:
“This bipolarity specifier attributes a diagnosis of bipolar disorder in patients who experienced an episode of elevated mood, an episode of irritable mood, or an episode of increased activity with at least 3 of the symptoms listed under Criterion B of the DSM-IV-TR associated with at least 1 of the 3 following consequences: (1) unequivocal and observable change in functioning uncharacteristic of the person’s usual behavior, (2) marked impairment in social or occupational functioning observable by others, or (3) requiring hospitalization or outpatient treatment. No minimum duration of symptoms was required and no exclusion criteria were applied.”
People sleeping less, talking more, and doing more. This is how mental illness is now being defined in psychiatry’s leading journal.
One of the dead giveaways that this article is bipolar diseases mongering is the sentence:
“No minimum duration of symptoms was required and no exclusion criteria were applied.”
This means that any person who has a suddenly angry, agitated, or elated response to an environmental trigger (like a big fight with a family member or winning the lottery) or who took cocaine would be labeled bipolar.
This would also mean that if they had a reactive episode of emotional dysregulation, the reaction would be labeled a bipolar episode. This makes almost anyone who has borderline personality disorder suddenly bipolar.
Also, 23.2 percent of their subjects who had experienced episodes of elevated or irritable mood triggered by antidepressants were also defined as bipolar. This is almost comical. Irritibility is a common side effect of drugs like prozac and has absolutely nothing to do with bipolar disorder (unless tranquilizers cure mania, because they sure do cure that side effect).
As evidence for the overall effectiveness of the PhARMA marketing campaign, the word bipolar, in the sense advocated by this piece-of-you-know-what study, is showing up in common discourse everywhere - particularly among young people describing their unpredictable and volatile classmates. You can even hear the word used as a synonym for moody in pop songs (e.g. “Hot and Cold” by Katy Perry).
"Someone... call the doctor - Got a case of love bi-polar"
The drug companies have really done a masterful job in bastardizing the diagnosis of real bipolar disorder, which is a serious mental illness. The harm to both the field and to patients alike has been staggeringly immense.
In response to this article, I wrote a letter to the editor of the Archives co-authored by my partners in crime-solving Drs. Peter I. Parry, Robert Purssey, Glen I. Spielmans, Jon Jureidini, Nicholas Z. Rosenlicht, David Healy, and Irwin Feinberg. It was published in the June 2012 issue of the same journal, and made a lot of the above points.
In the rebuttal to our letter, printed in the same issue of the Archives, the authors, using a number of old debating tricks, avoided actually addressing the criticisms in the letter and denied that they meant to conclude from their "study" that which was highly implied by their journal article.
Please keep in mind that when journals publish letters to the editor that are critical of one of their published studies, they allow the authors of the original study to respond to the criticisms, but that is where it ends. They do not give letter writers the chance to respond in the journal to the rebuttal. So I’m doing it here. Next to what they wrote in said rebuttal, I will provide my own commentary. Their rebuttal is in italics.
We are pleased to respond to the points raised by Allen et al, some of which take material out of context and quote news media articles beyond our control. For example, the letter states that “The message is that almost half the patients with a major depressive episode have undiagnosed bipolar disorder and are ‘not receiving necessary mood stabilizer treatment.’” The authors are well aware of exactly how the news media were going to interpret their study. Ditto doctors who read the article.
The drug companies have apparently taught these authors that their readers almost always ignore the disclaimers that they list next in their rebuttal. The article is designed to give a very specific “take home message.” The success of this strategy is illustrated by those very news stories over which they are now saying they have no control. Of course they don’t need to have direct control to achieve this goal.
Our actual statements are: "Based on these studies and the major differences in treatment guidelines for MDD [major depressive disorder] and bipolar disorder, we recommend that, among patients with MDEs [major depressive episodes], the presence of bipolar features, including all those with significant predictive value reported in this study, should be investigated carefully before a decision is made to prescribe antidepressants. If patients exhibit bipolar symptoms that impair everyday functioning, treatment with a mood stabilizer or an atypical antipsychotic may be useful." The take home message from what they “actually said:” exactly what we said it was. This paragraph subtly equates "bipolar features" with agitation seen in major depressive disorder - a fact nowhere in evidence.
This conflation is even more pronounced in the abstract of their original article (the short summary at the beginning of the article which is usually the only thing that most busy physicians actually read). That introduction states "Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers." This sounds like the article is going to demonstrate unrecognized signs of bipolar disorder and will "orient" anyone who reads the whole thing to think along those lines.
They assert that “The study’s findings are based on a ‘bipolar specifier’ requiring ‘no minimum duration of symptoms’ and ‘no exclusion criteria,’ ” and that “Any subject who came to psychiatric attention with an angry, agitated, or elated response to environmental triggers or psychoactive substances might have met criteria for ‘bipolarity.’ ”
The criteria, stated in the “Methods” section of our article,1(p793) were (1) an episode of elevated mood, an episode of irritable mood, or an episode of increased activity with (2) at least 3 of the symptoms listed under Criterion B of the DSM-IV-TR …The minimum duration of symptoms required for a hypomanic episode was 1 day. Here the authors are flat out contradicting themselves! I quote from the original article itself: “No minimum duration of symptoms was required and no exclusion criteria were applied.” (page 793). And exclusion criteria in the article do not exclude active drug abusers, which we brought up and which the authors just ignore in their rebuttal.
We assessed the duration reported for hypomanic episodes in 5 groups. Among subjects with major depressive episode with hypomanic episodes, 7.8% reported episodes of 1 day’s duration; 2 to 3 days’ duration was more frequent than 4 to 6 days. Even if they did have a minimum duration criteria, the DSM criteria for even a hypomanic episode is four days. Really, one day? In patients who met criteria for major depressive disorder? Riiiight.
…associated with (3) at least 1 of the 3 following consequences: unequivocal and observable change in functioning uncharacteristic of the person’s usual behavior, marked impairment in social or occupational functioning observable by others, or requiring hospitalization or outpatient treatment. Neither the article nor the rebuttal tells us how the study doctors made the determination that there was an unequivocal “change in functioning uncharacteristic of the person’s usual behavior. “ Especially since under their rules you only have to agitated (giving them the benefit of the doubt on their contradiction) for a single day, and if you took cocaine or had a big fight with your mother, you might have an unequivocal change in your “usual” functioning.
What the phrase is supposed to mean in the context of bipolar disorder is that the patient’s functioning has unequivocally changed under any and all environmental contingencies. They would have to be more reactive than they usually are to all situations to a similar degree.
So how would the study doctors know this? Did they take the patient’s or a family member’s word for it? I can tell you beyond a shadow of a doubt that patients rarely really understand what psychiatrists mean by this phrase. The only way a doctor can know this is the case is to observe the patients several times over several weeks, both during and outside of the specified time period.
In addition, even a close approximation would require taking an extensive psychosocial history including evaluating the subjects' current environmental stresses as well as an exploration of the nature, past history of, and current status of the subjects' relationships with spouses, lovers, parents, and children. Maybe the doctors involved in carrying out the "study" did that, but I doubt it, because doctors like these tend to denigrate the importance of such factors in favor of “disease” explanations. And it would take a LOT of time.
No exclusion criteria for manic/hypomanic episodes associated with antidepressant or other drug use were applied. So people who got agitated from a side effect of an antidepressants were not excluded by their own admission. Someone gets a side effect from a drug, and that proves they are manic?
Importantly, the initial eligibility criterion was that patients have presented to clinical settings for evaluation and treatment of a major depressive episode per DSM-IV-TR criteria. These sequential criteria, applied by senior psychiatrists in each country, are entirely inconsistent with the assertion that the psychiatrists conducting the assessments enrolled “any subject who came to psychiatric attention with an angry, agitated, or elated response to environmental triggers.”
The statement that 23.2% of subjects experienced elevated or irritable mood triggered by antidepressants did not “define the subjects as having ‘bipolar disorder.’” Rather,it addresses the DSM A criteria, which are essential, but not sufficient, for diagnosis of bipolar disorder. As Figure 1 in our article shows, mood lability while taking antidepressants occurred in 55.8% of bipolar specifier–positive vs 23.0% of bipolar specifier–negative subjects (odds ratio, 1.7;95% CI, 1.4-2.0) and mania/hypomania while taking antidepressants occurred in 37.2% of bipolar specifier–positive vs 3.4% of bipolar specifier–negative subjects (odds ratio, 5.7; 95% CI, 4.4-7.5). Sorry, but with this paragraph the authors are still implying that their subjects MAY be bipolar, and assumes precisely what the article is supposed to show—that a patient who is agitated when depressed could have a manic symptom. So if patients with an agitated depression are more likely to become more agitated on an antidepressant than depressed patients without agitation, that is supposed to show that they might be bipolar? Only by circular reasoning.
Allen et al view their position as part of a “debate” about the “ever-widening bipolar spectrum.” We consider data, not debates, as central to the progress in the scientific understanding of mood disorders. Ha! This is a brazenly outrageous statement. The “debate” is specifically ABOUT "data" like theirs—both its validity and what it means.
They make several references to borderline personality disorder. The BRIDGE study assessed for comorbid diagnoses in all subjects. Five hundred thirty-two patients (9.3%)met DSM-IV-TR criteria for borderline personality disorder. This large sample provides an opportunity to analyze patients who met borderline criteria vs those who did not. We are completing a manuscript that will provide useful evidence on this subject. Maybe they should have said this in the original article. But we know from the work of Zimmerman and others (My Psychology Today blogpost 12/11/11) that many patients who have borderline personality disorder are misdiagnosed as bipolar in clinical settings.
Allen et al cast unseemly aspersions that the BRIDGE study was a vehicle to promote sales of an antipsychotic drug sold by sanofi-aventis. sanofi-aventis has no antipsychotic with an indication for bipolar disorder. Here the study authors are being completely disingenuous. The misleading point is contained in the phrase “with an indication for bipolar disorder.” What they say is literally true - in the United States. Unfortunately, Sanofi does have an antipsychotic drug called amisulpiride (brand name, Solian). In fact, in the United States, it is not FDA-approved for any indication, let alone for bipolar disorder.
However, Solian is approved and widely marketed in Europe and Australia, and at least according to Wikipedia, used for bipolar disorder. (This may be why the study was conducted overseas). In addition, Sanofi also sells a preparation of depakote, which while an anticonvulsant and not an antipsychotic, is widely used in both actual and misdiagnosed bipolar disorder.
Besides, as I described in a blog post of 6/12/12, marketing for off-label uses of drugs for bipolar disorder is unequivocally rampant. Maybe the authors didn’t know this? NOT.
We know of no evidence that this was the case at any stage of development and execution of the BRIDGE study. Sanofiaventis ceased financial support for analyses of the study in 2010. All work subsequently conducted has been achieved by our local funds. How convenient. The drug company got out of the game just in time for the authors to claim they were not biased due to the funding source. Unfortunately, the original article says “The sponsor of this study (sanofi aventis) was involved in the study design, conduct, monitoring, data analysis, and preparation of the report.”
In addition, all of the clinicians recruited for the study received fees, on a per patient basis, from Sanofi-Aventis in recognition of their participation in the study. The key lead authors, all with significant Pharma connections, did not disclose their other pharmaceutical company ties. These authors: Allan H. Young, MD, Jules Angst, MD, Jean-Michel Azorin, MD, Eduard Vieta, MD, Guilio Perugi, MD, Alex Gamma, PhD, Charles L. Bowden, MD.
They should be ashamed of themselves.