study 329 xii – premature hair loss…

Posted on Tuesday 29 September 2015

I was hoping to move away from the Study 329 paper for a while, mainly not to run the boring in 1boringoldman into the ground, but something came up today that I thought was in need of emphasizing. During the 2 years writing the paper, there were a number of subplots along the way. As it became apparent that the suicidality issue was even bigger than we had imagined, we began to wonder if the Sponsors/Doctors had told the afflicted kids or their parents that the suicidal thoughts may well have been caused by the medication itself. Dr Healy wrote about this on his blog recently [Study 329: MK, HK, SK, GSK & History]:
What Happened to those Suicidal in Study 329?

In May 2014, the RIAT team asked GSK what the children who became suicidal in the course of Study 329 have since been told.  The consent form says that anyone entering the study would be treated just the way they would be in normal clinical practice.

In Study 329, the children taking imipramine were by design force titrated upwards to doses of the order of 300 mg, which is close to double the dose of imipramine given in adult trials by GSK or in normal clinical practice. In normal clinical practice it would be usual to inform somebody who had become suicidal on an SSRI that the treatment had caused their problem.
  • It is important to the person’s image of themselves, that they are aware this problem might have come from the drug rather than from themselves.
  • It is important that they be told that they are likely to react in the same way to any other serotonin reuptake inhibitors – including some antihistamines, isotretinoin and some antibiotics and that they should be cautious about such treatments in the future.
  • It is important the patient’s family be warned about this adverse event as some blood relatives will be more susceptible to commit suicide on an SSRI than the rest of the population might be.
Responding to our letter, GSK’s Dr James Shannon made it clear that 20 years later the company have still not informed any of the participants in Study 329. One reason he offered was that it had only recently been agreed these drugs posed risks. [One of the features of GSK’s response to the published study appears to be a public acceptance that SSRIs do cause suicidality in at least this age group]. But the key reason for not doing so that he offered was that:
    As I have mentioned in my earlier letters, it is standard in clinical trials carried out according to good clinical practice guidelines for our trial investigators and treating physicians to be responsible for patients’ medical care during and after a trial.  This would include the management of any adverse experiences that arise during the trial. Being closest to patients’ medical histories, they are best placed to do this and we are confident of their commitment to provide the care patients need.
This may be the first recorded appeal to the use of the Learned Intermediary doctrine in clinical trial settings. One lesson of the 329 story is that without access to data, the learned intermediary doctrine is supremely dangerous for patients – and for doctors…

And these "Learned Intermediaries" in this instance happened to also be authors  on this article, authors who have remained mute throughout. In fact, the public acknowledgement of suicidality as an adverse effect has only come from GSK in response to our recent article [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. Back in 2004, Dr. Keller seemed more focused on the authors’ public faces than their study subjects:
Sitting in the midst of a Maelstrom in 2004 when New York State were suing GSK for Fraud, faced with demands to “modify” Study 329, on June 13 Marty Keller emailed some of his co-authors to get a united position about what they would say to GSK about the modification:
    … that [it must be] 100% clear in this paper that there is no way to read it and think that 329 is being criticized and that it was not written with complete integrity and accuracy given the data we had and should have had…..  We also want it to be crystal clear that any new data or analyses, case report forms, narratives etc. you have worked with since 329 was published, was not made available to the 329 investigator’s by SK, otherwise we could look foolish, naïve, incompetent or “biased” (the most likely accusation that will be made) to present things in a way that was favorable to SK, disregarding our responsibility to the proper scientific method,  to the public, children and their families.
So as MK & GSK see it, while the Learned Intermediary Doctrine rules, he and his colleagues have a responsibility to their patients.  Someone needs to do the right thing by the Paxil 12…
Focusing back on the kids, there was an article published in today’s International Business Times that has some answers:
International Business Times
By Amy Nordrum
September 29 2015
I’m not even going to attempt to summarize this article. It needs a full reading, as do most case studies. The reporter interviews several people, now in their thirties, who took Paxil as teenagers. They describe how the Adverse Effect described in our paper feels on the inside. Some figured out it was the drug at the time, some didn’t. And in the latter case, the reaction to our article was as predicted in Dr. Healy’s post. I’ve seen a number of such patients who have had persistent self image problems from SSRI Adverse Events they didn’t know were from the drug. Like the case studies in Nordrum’s article, they were both relieved and enraged when they found out that the medication was responsible.

Except for the recent Swedish study [see an innovative design… ], the population studies haven’t detected the suicidality Adverse Effects. I think this article probably speaks to why. Most patients who have this kind of reaction either recognize it or are told about it by others and stop the medication and move on. Thus, there’s no way for them to show up in a population survey. I was surprised at the actual incidence in Paxil Study 329 – greater than 10%. This is one place where the clinical trial, carefully reported, can tell us something missed in other venues [because the subjects are so closely watched].

As to the "Informed Intermediary" argument. The "Intermediaries" have been kept in the dark too. Since our article came out, GSK, the JAACAP, and Keller have acknowledged publicly the "tendency towards suicidality" in adolescents taking SSRIs as a way of saying our article says nothing new. To my knowledge, that’s somerthing of a new tune for each them [even though they still stand by their original versions]. That is some pretty powerful spin. But, if that’s what it takes to finally get their acknowledgement, so be it. That’s what we’ve been wanting them to say for well over a decade!

This was, however, more spin than I could tolerate:
GSK voluntarily published the Paxil trials through a new program called RIAT, which stands for Restoring Invisible and Abandoned Trials. RIAT aims to nudge clinical research and drug development toward greater transparency and data sharing, and GSK was the first company to participate.
I can’t blame the author. GSK has indeed been taking credit for our article. But it’s a bit like an abcessed tooth claiming it pulled itself. The data coming our way was hardly "voluntary." It took the 2004 New York settlement, a challenge by Peter Doshi, over a decade of widespread pressure and lawsuits, months of our own group’s negotiations, and viewing the data through a periscope to get that data. So it’s kind of hard to swallow that version and turn the other cheek [this was the leading cause of premature hair loss among our group over the last two years]…
    September 29, 2015 | 7:40 PM

    You need a new moniker. How about 1brilliantoldman?

    Katie Tierney Higgins RN
    September 29, 2015 | 10:21 PM

    I wonder if any of the Paxil 12 were subsequently diagnosed bipolar, like so many kids in the Boston area whose adverse response to SSRI’s was heralded as , “unmasking bipolar”. Bad news/good news ? Well, good news for the mood stabilizer & antipsychotic drug market that the epidemic of childhood/juvenile bipolar coincidentally opened.

    Could the reasoning for drop outs who were experiencing adverse reactions to Paxil have been substantiated by saying these kids had *bipolar* which disqualified them from participation in this study?

    September 29, 2015 | 10:48 PM

    You do need to move on. You’re starting to live up to your name 🙂 Usually you don’t.

    Bernard Carroll
    September 30, 2015 | 12:30 AM

    Now that GSK agree the suicidality problem exists with their drug Paxil, do they recognize their responsibility going forward? Do they have the good sense to bring Medical Affairs front and center to call the shots over Marketing and Legal? Do they understand what they need to do?

    The scientific need is for a GSK-funded, independent study of the predictors of Paxil-induced suicidality and other major behavioral side effects (akathisia, completed suicide, homicide). The study should include genetic markers in addition to clinical predictors. Medical Affairs receives adverse event reports from the field, and those cases could be made available to the project. The results should be clinically pertinent.

    This isn’t rocket science, you know, but it could be a good-faith step by GSK.

    September 30, 2015 | 2:07 AM

    Ah, that word spin.

    Laden’s favourite, it would appear 🙂

    September 30, 2015 | 9:33 AM

    It’s outrageous that GSK would even attempt to spin this as positive for them… They must be really scraping the barrel if they need to spin a study that harmed (and killed) kids as something positive in terms of transparency. They really are the lowest of the low. Sociopaths galore.

    James O'Brien, M.D.
    September 30, 2015 | 12:14 PM

    I think at this point it’s an impasse.

    AACAP can choose not to retract the publication of the article.

    And doctors can choose not to pay dues to the organization and not give them respect as they’ve forfeited any claims to it.

    The antidote to the appeal to authority is to claim, rightly, that respect is earned not deserved.

    BTW boring doesn’t just means tedious, it also means digging a hole deep. I feel that a big bloated dysfunctional zeppelin has been popped so thank you for the public service.

    felonious grammar
    September 30, 2015 | 6:37 PM

    There’s nothing like being told that you’re defective, because you lack “resilience”, because you lost the genetic lottery on behalf of a drug induced state to make ya’ wanna’ say, “Thanks, psychiatry. Thanks a lot. Couldn’t have been worse without ya’.

    October 1, 2015 | 10:22 PM

    As Mickey says: “I’ve seen a number of such patients who have had persistent self image problems from SSRI Adverse Events they didn’t know were from the drug.”

    There are literally millions of people who think they “need the drug” for life because they had difficulty withdrawing from it. They believe this proves they have a “chemical imbalance” or a progressive brain disease or a deep psychiatric flaw, not to mention those, as Katie Higgins noted, who were diagnosed “bipolar” and put on unnecessary drug cocktails.

    This is affecting millions, for years, and years. It’s truly a public health issue. What can medicine do to remedy this?

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