Disease Mongering in a Respected Journal and Plausible Deniability

In my post of August 31, 2011, Plausible Deniability, I illustrated how doctors under the sway of pharmaceutical companies widely distribute a completely invalid “take home message” to readers of journal articles and those who listen to academic-sounding presentations, while simultaneously providing themselves with an “out” so that they can deny doing just that.  Some of these strategies have been created from information gathered from the drug company marketing departments' intensive research into physicians and the way they think (see post: Physicians As Unwitting Research Subjects, 1/3/12). 

Apparently, these strategies are widely disseminated to physicians and researchers working with Pharma.  They are just too common.  A great example occurred in a rebuttal to a letter to the editor that I and several of my partners in crime (Peter I. Parry, Robert Purssey, Glen I. Spielmans, Jon Jureidini, Nicholas Z. Rosenlicht, David Healy, and Irwin Feinberg) managed to get published in the June 2012 issue of the Archives of General Psychiatry.  The Archives is considered one of the two top journals in psychiatry.

The letter was highly critical of a study that was published in a previous issue.  The article was one I blogged about in a previous post (More Disease Mongering in a Respected Journal, 8/13/11).  The gist of our published letter was described in that post, and I will not repeat it here.

However, let me use the rebuttal to our letter, printed in the same issue of the Archives, to illustrate how the authors avoid actually addressing the criticisms in the letter and deny that they meant to conclude from their "study" that which was highly implied by their journal article.  The latter issue is what I previously referred to as plausible deniability. 

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.  (It is a situation similar to that of reporters at a presidential press conference who are not allowed to ask follow-up questions).  So I’m doing it here.  Next to what they wrote in said rebuttal, I will provide my own commentary.

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 readers will routinely ignore the disclaimers that they list next in their rebuttal – a case of plausible deniability.  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 the article (the short summary at the beginning of the article which is usually the only thing that most busy physicians actually read). The 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 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 for a 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 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 unpleasant situations to a similar degree. 

So how do 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.  


Even a close approximation would require taking an extensive psychosocial history including evaluating 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 they 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.

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 complete weasels.  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 my 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. 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. Actually, 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.