The Troubled Life of Study 329: Consequences of Failure to Retract

David Healy, MD
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If someone were to ask the surviving authors of Study 329 the question: “Knowing what you know now, if you had to do it over, would you agree to participate in that study again?”, many would probably say no. The real title of Study 329 was “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial.” It was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in July, 2001. Although it is probably fairly typical of medical research studies, it has been plagued by more than its share of troubles. Next week, fourteen years and two months after it was published, it is about to take yet another hit, when the Restored version is published.

There were many obstacles to doing the work to write Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression. The biggest was getting access to the data.  It took years to get the data, months to analyze it, and another year to get a version of the restored study that BMJ felt comfortable with. The “Restoration” of Study 329 may not have occurred if Study 329 had been retracted. If JAACAP had heeded the earliest calls for retraction, much of the unfortunate history of Study 329 could have been avoided.

In hindsight, the authors may wish that they had not been so adamant that retraction was unthinkable. Of course, there are probably many flawed studies that remain un-retracted. Many of the pitfalls into which Study 329 fell resulted from bad timing, coincidence, an astute and determined journalist, a Senator who found conflicts of interest in medicine unacceptable, and the unwavering commitment of a small group of medical experts who refused to give up and go away. How could those authors have foreseen?

Study 329’s problems started to surface right after it was published. Several doctors wrote letters to the JAACAP Editor with probing questions, mostly centred on the psychiatric side effects of paroxetine, and the measures used to claim its efficacy in treating adolescents.  The authors responded and the questioners did not pursue their concerns further. Except one. Child Psychiatrist Jon Jureidini, M.D. from the University of Adelaide remained convinced that there were serious methodological problems hiding real harms, and he never stopped pushing to expose the truth.

After Study 329 was accepted but before it was published, a Wyoming jury awarded $6.4 million to the relatives of retired oilman Don Schell (Tobin v. SmithKline Beecham). Forty-eight hours after Mr. Schell had been prescribed paroxetine (Paxil), he put bullets through the heads of his wife, Rita, his daughter, Deborah, and his granddaughter, Alyssa. Then he shot and killed himself. The jury decided that Paxil was responsible for the tragedy.

Scottish journalist Shelley Jofre, having learned about the Schell case, did some research on the drug and arranged to do a program on paroxetine, known as Seroxat in the U.K., for BBC’s Panorama. The segment, Secrets of Seroxat, aired in October 2002. It revealed that the drug can cause suicidal and violent thoughts and behaviours, and that many people experience serious withdrawal problems. The show received such a huge public response that a second episode was developed, Emails from the Edge.

Following Secrets of Seroxat, the U.K. public was highly sensitized to the potential problems associated with paroxetine. In December of the year that Emails from the Edge was broadcast, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory warning to physicians against prescribing SSRI antidepressants, including Seroxat, to people under age 18.

In June of 2004, New York State Attorney General Elliot Spitzer filed a lawsuit accusing British drug giant GlaxoSmithKline PLC of “repeated and persistent fraud” for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents. Evidence was largely based on documents that had come to light in the Tobin case. The suit was settled for $2.5 million plus a promise by GSK that they would make their drug trial data accessible. Later that year, the FDA required that a “black box” warning label be added for all SSRI antidepressants, including Paxil.

In 2008, US Senator Chuck Grassley investigated serious violations of conflict of interest policies among high-profile academic psychiatrists, including Martin Keller, lead author of Study 329, and three of his coauthors. Senator Grassley’s investigation brought attention to the fact the nominal authors in many research studies are not the real authors. This was the case in Study 329. GSK hired a “ghostwriter”, Sally Laden of STI, to write the study article under GSK direction.

Over the next few years, many lawsuits involving suicidality and violence caused by paroxetine were settled. In addition, Paxil and other SSRI drugs became the target of lawsuits for causing birth defects. The FDA recognized suicidality and violence as side effects of SSRI antidepressants in all age groups and expanded the required “black box” warning.

In 2012, the U.S. Department of Justice brought an action in U.S. District Court to recover damages and civil penalties from GSK under the False Claims Act, and damages and other monetary relief under common law and equity for causing the submission of false or fraudulent claims to federal health care programs. Three drugs were implicated, including Paxil. This action was settled for $3 billion, the largest settlement of its kind.

All in all, the past decade was not an unqualified success for Paxil and its manufacturer. Still, the conclusion of Study 329, that “Paroxetine is generally well tolerated and effective for major depression in adolescents”, has stayed officially intact, since the study was never retracted, and has been widely cited.

In 2013, Peter Doshi and a number of other researchers published a paper in the BMJ entitled “Restoring invisible and abandoned trials: a call for people to publish the findings.” This is part of a larger campaign to make all data from drug trials available for public scrutiny.

In August, 2015, BMJ accepted for publication a new analysis of the data from the original Study 329. Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression will be published online sometime the week of Sept 14, and in the hard copy journal later that week. The new team of authors, including those most active in lobbying for retraction, has taken the same data and reached startlingly different conclusions than the original.  Their conclusions should lead us to reassess our assumptions about drug safety regulation.

Stay tuned to this blog as the details continue to unfold.  See also 1boringoldman for a thorough ongoing analysis of this remarkable saga…

Today on the Study 329 site we have added a new section under “Background” which provides a summary of the attempts to get the original Study 329 retracted, together with links to the underlying documents.

13 COMMENTS

  1. Interesting. A few thoughts:

    – If a study like this gets retracted or proven “wrong”, does it cause significant harm to the careers of the principal authors? I would imagine it hurts or at least embarrasses, and that may be part of all the resistance.

    – While this exposure of Study 329 is a positive step, the most important thing seems to be to implement a standard process for making data publicly available from all studies, and clearly identifying outcome measures before a study begins.

    – Regarding Mr. Schell and the tragic murders attributed to his taking Paxil, I hesitantly wonder how they could know in any individual what was the effect of a drug and what was other factors? Juries often make emotional faulty decisions and to me this conviction sounds like it could be a mistake. In two or three days, a lot can happen. Maybe he mistakenly expected the drug to work suddenly and when it didn’t, or when some other life stressor occurred, he snapped. Maybe he’d already been planning the murders for some time. His murders could have had nothing to do with Paxil per se. I believe that Paxil could cause suicidality, but that one could only see that clearly with a larger, statistically strong well-done study.

    • I think I can briefly address your misgivings about verdicts that found the drug guilty, as a psychiatric clinician (1988-2010) who witnessed the advent of Randomized Clinical Trials, and the profound shift from honoring the expertise of a seasoned clinician to worshipping RCTs as Gold Standard evidence of rigorous scientific study– that trumps the expert opinion of a seasoned clinician.

      The early warning bells were sounded by *boots on the ground* front line, well credentialed psychiatrists, who had the courage to challenge what was already heralded as bottom line evidence of both efficacy and safety of the wonder drugs– SSRIs and new atypical anti-psychotic drugs. I’m talking at least 20 years ago. Harvard trained psychiatrist & professor Joseph Glenmullen, for instance, who published his concerns in 2000, “Prozac Backlash”, had already met stoic resistance from his colleagues to engage in debate and further study of SSRIs. Here are a few links that support the significance of Glenmullen’s findings– http://www.finance.senate.gov/:

      http://www.lawyersandsettlements.com/articles/ssri/paxil-suicide-risk2-01961.html?utm_expid=3607522-8.uTwqV-N-RqmmAyO2kCf6lA.0&utm_referrer=https%3A%2F%2Fwww.google.com%2F#.VfEHB7SbIRk

      You will find that all opposition to his expert witness testimony ( his writing and his depositions) that accuses the drug, is centered around the defense of the Gold Standard- RCT’s– ; that he, the seasoned clinician is lacking credibility in the most fundamental sense , for his heretical views? Yeah, before the turn of the century, the doctrines that define psychiatry as a REAL science were circulating– briefly:
      1) Mental illness is caused by chemical imbalances in the brain that can be corrected with psych drugs
      2) and RCTs are the basis for the new treatment guidelines.

      As Healy points out, RCTs are the ideal way to hide adverse effects– Why? because the clinical trial looks at one aspect of the drug’s action (a predetermined target symptom of a DSM disorder, or soon-to-be DSM disorder ), and ignores the other 99 things the drug is doing– It is a bit more complex than that with regards to the smoke and mirrors used to enhance efficacy outcomes and detract from adverse effects , but basically, RCTs are as potentially dangerous as the fabricated science that uses them to fortify the current very dangerous practice of biomedical model psychiatry.

      I witnessed the negating of patient adverse responses to these drugs– which is tantamount to watching so-called veteran psych clinicians yielding to psychiatric who insisted the drug was not the culprit– though – damn! The drug was the only new variable that could explain the adverse response. I witnessed intelligent people doubting what they saw in front of them– doubting their own clinical judgment and eventually considering common sense to be– *common*, not worthy of consideration now that we have rigorous scientific evidence– RCTs!

      Peter Breggin’s book “Medication Maddness” details the process he, and other psychiatrists employ as expert witnesses who cite the drugs– even in cases of tragic murders. The underpinning hypothesis that I see as the best way to explain the drug’s potential, is a combination of the numbing, the extreme agitation and a dissociative process- occurring in someone who had no reason to doubt the drug, or rather no frame of reference that would alert them or their significant others to the possibility of experiencing this level madness/psychosis from a drug prescribed by a trusted doctor. Peter Breggin calls this a *spellbinding* effect–.

      So, here we are– the evidence is strong and compelling. The warnings come from well educated, experienced psychiatrists– but unfortunately they are attacked, vilified by their colleagues– silenced as heretics. Yet, they are the only remaining vestiges of what was once the humanistic practice of treating vulnerable, suffering people by way of *medicine*–.
      There have always been good psychiatrists, but these few today, are threatened with extinction — in direct relationship to the extent to which they challenge the current paradigm of care and threaten the empire that grew from it’s creation.

      Is disclosing the raw data enough? See the four part commentary on this mantra–

      http://davidhealy.org/sense-about-science-follow-the-patient/

      ~Katie

    • To address the other two questions:

      – in the case of retraction authors rarely are subject to any consequences. In some cases this is justifiable – when the publication is a result of an honest mistake (which happens). But there are clear cases when fraud was committed and nothing really happens. The worst case scenario for the person committing the fraud is losing face in front of scientific community and therefore further funding and employment possibilities. Which sometimes happens in basic science and for young researchers but rarely when established clinicians are involved. In fact there is no clear mechanism for punishing such behaviour that I know of and it’s mostly the hope that tarnished reputation will do the job. It often doesn’t.

      – in case of transparency – the current state of affairs is ridiculous, inexcusable and can only be explained by the politicians and regulatory bodies being in bed with pharma. There are some organizations like AllTrials which are fighting for more transparency, independent bodies which document problems with studies such as Retraction Watch and that critically re-analyse the data or document side effects (like Cochrane and RxISK.org). But there’s no coherent mechanism right now to force clinical study authors to follow the guidelines and publish all the data or in fact publish at all. The preregistration is largely on voluntary basis and even when journals claim to require it as a standard they often do not follow their own rules. In other words: it’s a hot mess.

  2. Thank you, David, for working to expose the truth. The SSRI’s and SNRI’s can and do have serious mind altering and withdrawal effects. And the American psychiatric industry has DSM-IV-TR misdiagnosed millions of Americans, including many children, as “bipolar” due to this type misinformation. And because the psychiatrists / psychologists refuse to believe their patients “your drugs make me sick” complaints. And, of course, Biederman’s behavior. And how does the APA cover up this almost unfathomable in scope malpractice? They change the DSM5, making this completely iatrogenic pathway to “bipolar” appropriate standard of care. Truly, the inmates are running the asylum now.

      • I’ve always wondered what the difference is between “clinical” depression and other, theoretically non-clinical depression is. I suspect that what is going on there is that psychiatrists have figured out they can bullshit the system for a few more dollars, and drag out the “medication adjustment” period for a few more days, and fill the beds a little longer, and so on and so forth, with Medicare dollars as the bottom line and goal about it all. Is clinical depression “real depression”? Is non-clinical depression “real depression”? Or does it take some legitimizer in a lab coat to say so for your feelings to be real? Does a Medicare billing form make the difference?

        • Hi Eric,

          I think it’s a confidence trick.

          From the book ‘Depression Delusion’ (by Dr Terry Lynch):

          “Commenting on experiences of his patients that clearly did not fit into the narrow medical model, Irish psychiatrist Professor Ivor Browne   wrote in his 2008 book Music and Madness:

          “It was experiences like this which taught me how bogus is the concept of “clinical depression”. The idea that there is a chemically mediated   form of depression which is an “illness”, quite separate from the sadness and depression which are part of the slings and arrows of ordinary life, is manifest nonsense. [125]””

  3. Dr. Healy:

    Thanks for the heads up about the new study being published on Sept 14. That is coming up very fast. I hope the authors will not face a backlash.

    You write: “The new team of authors, including those most active in lobbying for retraction, has taken the same data and reached startlingly different conclusions than the original. Their conclusions should lead us to reassess our assumptions about drug safety regulation”

    Are you referring to our assumptions about drug safety regulation as it relates to this class of drugs only (SSRI’s)? Many of us have loved ones who have been harmed or continue to be harmed by other classes of drugs. If this has implications for the testing and regulation of all psychiatric drugs I would be very happy but not as happy as it it affected more than our assumptions but led to actual changes in the way we regulate drugs.

    Assuming optimistically, that this changing of ‘assumptions’ started to warm people up to the idea of reforming the way we regulate drugs, I imagine that every country already has its own drug safety regulations/standards in place. Where does one begin to get them to do their jobs better or differently? What is the U.K’s version of the FDA and will this revised study impact the UK only?

    Is there an international agency in existence that is responsible for drug safety of all psychiatric drugs sold worldwide? If so, will that agency be affected by a high profile case such as this? Some of us who have family members who have been harmed by psychiatric drugs are very keen that the US not export failed drugs to developing nations.

    Using big Agriculture as a parallel, the US banned DDT after Rachel Carson’s pioneering study on the affects of pesticides on local bird populations but developing countries like Mexico continued to use DDT, including on produce that was being imported back into the US. My guess is that existing trade agreements make it impossible for Mexico to refuse to purchase banned pesticides from the US and with the Trans Pacific Free Trade Agreement spearheaded by the Obama administration, it may be even harder for developing countries to enforce regulations or ban harmful consumer products including psychiatric medications. In fact, I was surprised to find, on a website dedicated to stopping the fast track legislation at: https://www.stopfasttrack.com/#video, there is not a single organization representing drug safety or ‘green medicine’ . In other words labor, the environment, and sustainable farming interests are all represented but not consumer/drug safety! Why aren’t consumers represented at this important global discussion?

    Also, I had no idea that former New York State Attorney General Elliot Spitzer filed a lawsuit against GlaxoSmithKline in 2004. I knew he took on the mob, AIG and other ‘too big to fail’ corporations that were engaging in securities fraud. Too bad about the prostitution scandal that ruined his public career.

  4. They should all be put on trail for crimes against humanity.

    Glaxo Is Testing Paxil on 7-Year-Olds Despite Well Known Suicide Risks

    The Nuremberg Code

    And I have this buddy with a drinking problem and a diagnosis of OCD, he keeps relapsing, he gets wasted on booze for a few days then goes back to rehab where they stick him on Paxil every time and it gives him this total deer stuck in the headlights look.

    I would like to send his parents this link davidhealy.org/out-of-my-mind-driven-to-drink

    The majority of young people I see that check into drug and alcohol rehab were psych med kids. What do they do ? They give them more pills.

  5. Thanks for the links, cat. I have observed the same myself.

    There’s probably an epidemic of citizens that didn’t have anything really wrong with them to begin with, suffering very badly as a result of exposure to SSRIs.

    I think it’s a Civil Rights Issue.