the fiction – and another thing… »
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the fiction…

Posted on Friday 16 January 2015

University of Chicago Statistician Robert Gibbons was a voting consultant on the 2004 FDA Pediatric Advisory Committee that elected to add the Black Box Warning to the labeling of the Antidepressants:
    Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children and adolescents in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…
Since that time, he and Dr. John Mann, a Professor of Psychiatry at Columbia, have challenged that Warning with a steady stream of articles occasionally joined by other groups. Here’s the summary from their most recent offering:

The Relationship Between Antidepressant Initiation and Suicide Risk
Special Reports, Psychopharmacology, Suicide
Psychiatric Times
By Robert D. Gibbons, PhD and J. John Mann, MD
December 31, 2014
[full text on-line with free registration]

Summary
The data show that in adults, antidepressants appear to protect against suicidal events. SSRIs are associated with lower overall suicide rates compared with other classes of antidepressants [eg, TCAs]. Antidepressants are effective in reducing symptoms, which, in turn, mediates suicidal events in adults and the elderly. This does not appear to be the case for youths, for whom antidepressant medications can reduce the severity of depression but appear to have no effect one way or the other on suicidal thoughts and behavior. Conversely to what is seen in adults, it may be that aggressive-impulsive traits play a more important role in youth suicide than does depressed mood. The impact of antidepressants on these traits remains unclear. Youth suicide may also be potentially related to illicit drug use and social factors, such as bullying, that are not directly affected by antidepressants.

The black box warning and the earlier public health advisory have shown that discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior. Careful monitoring and treatment of depression and monitoring suicide risk in children is clearly essential. Overall, the clinical evidence is that the majority of patients, young and old, benefit from antidepressants, without increased risk of suicide.

Ten years after the introduction of the black box warning, it is time that the FDA reevaluates this decision and that the results be made public. Moreover, the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment.
Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.
You would think that as much time as they’ve spent on this quest, they’d at least understand the domain of the FDA’s power. After approval of a new drug based on proof of efficacy and safety, the FDA is charged with monitoring safety ongoing, even pulling drugs from the market that prove to be toxic. The obvious reason is to alert physicians to the risks using the drugs as new information becomes available. Drugs are only approved for specific conditions, and manufacturers are constrained from advertising for anything except the FDA approved uses. On the other hand, the FDA has absolutely no authority over how physicians actually prescribe the drugs. So first, there’s the simple matter of what Drs. Gibbons and Mann are asking the FDA to do, "… the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment." That’s not remotely an authority the FDA has or should ever have. The FDA doesn’t give opinions about risk/benefit ratios or treatment. That’s for the medical profession to determine with clinical use. The FDA simply certifies minimal efficacy based on a few short term clinical trials, and reports on the adverse events from the trials and later spontaneous reports. It’s actually an absurd request, well outside either the charge or expertise of the FDA. Surely the authors know that. So one has to wonder why they would even propose such a thing?

Then there’s a fundamental misunderstanding of the practice of medicine that runs throughout their ten year thread of challenges. The information about clinical decisions comes from many places: the doctor’s own experience, the experiences of others over time, clinical trials and other studies, the wisdom of the ages, the specifics of the patient being treated, etc. But at the end of the decision making process, it’s only the patient in front of the doctor that’s being treated – not some nameless group defined simply by age and diagnosis. Just that one patient. Gibbons et al argue that because antidepressant prescription rates fell [or didn’t continue to climb] with the Black Box Warning, kids are being deprived of necessary treatment. And they even propose motives. First, that "discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior" as if that’s what the FDA did or was tasked to do. Again, the FDA warned that these drugs can, at times, be associated with suicidality – as a drug effect! That’s their job – drug effects. What doctors do with the information isn’t the FDA’s business [or Dr. Gibbons’]. The FDA is supposed to help us by telling us what bad things can happen – and that’s what they did. And further, these authors propose to know the psychology and motives of doctors, that we were afraid to prescribe these drugs for inappropriate reasons [like getting sued] because of all the publicity about the warning – so we are withholding treatment. They ignore the much more obvious explanation that knowing of the danger, we became appropriately more cautious ["Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…"]. And they imply an efficacy for antidepressants in teens that’s mythologic. Only two of the antidepressants were approved for teens, and they had anything but a robust effect. They apparently think that population statistics should determine the treatment of any given patient. If that’s the case, we don’t need doctors, we only need computers and statisticians.

And then there’s this decade-long cascade of papers with arguments that keep changing as they attempt to prove their point using population statistics on large databases or a meta-analysis of other people’s studies [with no public access to the data]. There are at least fifty other posts on this blog looking at the details in these papers [just put "gibbons black box" into the search box below]. In particular, see persistence…. It’s about number 11. below, which has my letter [unpublished] and letters from two others that were ultimately published in the journal.

  1. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  3. Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
  4. Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
  5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
  6. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
  7. Brown CH, Wyman PA, Brinales JM, Gibbons RD.
  8. Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
  9. Barry CL and Busch SH.
  10. Gibbons RD, Mann JJ.
  11. Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
  12. Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
  13. by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
    15. by Robert Gibbons and J. John Mann
  15. by Mark Moran
  16. by Richard A. Friedman, M.D.
  17. Robert D. Gibbons, PhD and J. John Mann, MD

As I said last week:
    I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am sure were SSRI induced.
I’m suspicious that the six articles in 2014 [12.-17.] are harbingers of an effort to get the FDA to convene yet another hearing to revoke the Black Box Warning, now ten years after its adoption, based on the monotonous arguments in the articles listed here. Again from last week:
    They are proposing that warning the clinicians of a potential problem has lead to what they think is an error, so we shouldn’t warn the clinicians?? however rare?? They speculate that operating without being warned, they may ultimately help more people in their ignorance [or silence]?? And perhaps we shouldn’t warn our patients either, so they’ll follow our [proxied] advice?? There’s nothing I know about Medicine that supports that confusion of tongues. These highly placed doctors are not thinking like clinicians, and their group-think has no place in the hierarchy of Medicine as I know it. They’re not speaking the right language… Individual physicians have to construct an individualized risk/benefit estimate on every shared decision from a baby aspirin a day to dangerous and life threatening chemotherapy using known poisons. You can’t do that living in the dark about risk…
The majority of this four page Psychiatric Times piece is designed to bolster the fiction that the Black Box Warning was motivated to affect suicide rates rather than what it says: to warn doctors of Akathisia and suicidality – an idiosyncratic drug effect that afflicts some child and adolescent patients.
  1.  
    Bernard Carroll
    January 16, 2015 | 11:58 PM
     

    Thank you for underlining the point that the FDA doesn’t regulate the practice of medicine. It was never chartered to do that. The FDA’s charter is to regulate the claims of corporations that want to market medical ‘stuff’ – drugs and devices. As for Gibbons and Mann, for all their persistent digging they have never candidly examined the evidence that suggests too many patients were being given antidepressant drugs with little prospect of specific benefit and that the modest decline in rates of prescribing after the black box warning was actually a good thing.

  2.  
    Steve Lucas
    January 17, 2015 | 8:40 AM
     

    Persistence was a key word in a sales class I took as an undergraduate. The concept is that a sale is a sale and getting a sale because you wear down the customer is still a sale.

    Another sales concept is the straw man argument. You are not buying the product because you cannot afford the product is one we have all encountered when buying a car or other item. The straw man here is the FDA and government regulation. Government regulation is something we all hate so there is an instant bonding and acceptance of the concept that the government is withholding this valuable medication.

    This continues to show the sales orientation of pharma. The simple resolution to this problem would be allowing access to all of the data for this and other drugs. That will not happen as the lack of effectiveness, high drop out rates, and adverse events will be the fodder for numerous legal suits.

    Troubling is this noise creates questions for not only the doctor but for the patient. Doctors have lost much of their scientific orientation as they become more and more obsessed with the business of their practice. The result is fewer questions are asked which plays into the hands of pharma.

    Patient demands are driving doctors to distraction. I know a Pedi who regularly gets demands from schools and parents for ADHD medication levels that do not exist. Then they must deal with the abusers of these drugs, making helping a child very difficult.

    Medicine in this country has reached the point of buyer beware. The test and medications being given may be for the financial gain of the doctor, the practice owner, or a relationship with a drug company. Like any good sales orientated company a sale is a sale.

    Steve Lucas

  3.  
    Altostrata
    January 23, 2015 | 9:11 PM
     

    What’s striking to me, Mickey, is that you recognized akathisia simply by closely observing your patients without preconceptions that adverse effects of the drugs were so exceedingly rare the average clinician would never see them.

    I have one case after another where patients initiated on psychiatric drugs clearly were suffering from overstimulation — some outright akathisia — yet the doctor interpreted it as anxiety or some such and prescribed an auxiliary benzo or antipsychotic to compensate, compounding the misery.

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