A Milestone in the Battle for Truth in Drug Safety: Study 329’s Final Chapter Coming soon

David Healy, MD
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Arguably the most controversial drug study ever, Study 329, published in July 2001:

  1. Concluded that paroxetine was a safe and effective medication for treating major depression in adolescents;

  2. It is still widely cited in the medical literature, providing physicians with assurance about the usefulness of paroxetine;

  3. Though it was criticized by a few alert and concerned journalists and academics, their voices were buried by a tsunami of positive marketing and promotion by vested interests;

  4. This promotion resulted in a successful New York state fraud lawsuit against GSK;

  5. And resulted in 2012 in the biggest fine in corporate history – $3 Billion; and

  6. Nevertheless, the study remains unretracted.

Paroxetine Names Around the World

ParoxetineWC

In June, 2013 Peter Doshi and colleagues published “Restoring Invisible and Abandoned Trials: A Call for People to Publish the Findings” in the British Journal of Medicine (BMJ).

They referred to this proposed protocol as RIAT, and described its purpose as follows:

“Unpublished and misreported studies make it difficult to determine the true value of a treatment. Peter Doshi and colleagues call for sponsors and investigators of abandoned studies to publish (or republish) and propose a system for independent publishing if sponsors fail to respond.”

A team of researchers undertook to re-analyze the original data and publish a new analysis under the RIAT protocol.

In August, 2015, after a year and seven drafts, BMJ notified the team that their submission would be published in September, 2015.

This new study, Restoring Study 329: Efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression: restoration of a randomised controlled trialshould shock all who care about integrity in drug safety. Find out the inside story when a new site, Restoring Study 329, goes live.

This will be the first ever that studies are published with two completely different takes on the same data.

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This blog is a slightly revised version of a blog
that appears on DavidHealy.org

18 COMMENTS

  1. This study won’t mean much however it’s interpreted. Major depression is not a valid illness, and it’s close to chance whether different psychiatrists “diagnose” the same person with it.

    Below are reliability ratings from DSM IV and 5 field trials for Major Depression – they were in the 0.2 – 0.3 range, which is horrible. It means that more often than not such labels are applied arbitrarily and randomly.

    http://1boringoldman.com/index.php/2012/10/31/but-this-is-ridiculous/

    So if the same condition is not being studied across the population, what does it matter how this study is interpreted?

    It’s like reinterpreting a study on lions when most of the lions in the study were actually unicorns, dragons, and griffins.

    Until psychiatrists can reliably and validly identify “mental illnesses”, these studies should be ignored.

    • Well bpd, it is nice to see that you are quoting information from the website of one of the authors of the soon-to-be-published new version of Study 329, Dr Micky Nardo. When a study purporting to find an effective treatment for depression (whether or not it is reliably diagnosed, or even real) goes under the validity microscope, we should all care. Questionable research that poses as science is a problem. Inaccurate research findings that led to many young people being prescribed a drug that caused them suffering, damage, and death deserve a sober second look. All those multitudes of professionals prescribing paroxetine can benefit from a “second opinion” about what the research showed. At the very least, this might cause them to question some of their assumptions.

      • I’m glad you like my quote 🙂 The point is that however this data is analyzed or reevaluated, what it means is going to remain unclear because it is not based on a real illness entity.

        I agree that these studies may appear to show interesting trends and correlational relationships. In that way, they do matter because they affect attitudes and behaviors. But that does not mean that the studies themselves are accurate, reliable, or meaningful observations of anything.

        Major depression is always at the bottom of the barrel when it comes to DSM reliability ratings. When reading these studies, I’m always left wondering how these denuded statistics and meaningless labels relate in any way to what real individuals experience or to how doctors understand their clients.

  2. On the RTE (Irish radio/television) news website today, there’s another tragic homicide suicide with a depression treatment circumstance attached. This type of horror story was very rare before “antidepressants” came into common usage in Ireland.

    • A National Bureau of Economic Research study comparing changes in antidepressant use with changes in violent crime over time found that those countries with the largest increase in SSRI prescriptions saw the largest decreases in violent crime.

      People on antidepressants are more likely to commit crimes in the same sense that people in the hospital are more likely to die. Its not a treatment effect, its a result of the underlying problems that lead the person to take an antidepressant. In spite of the popularity of the myth of antidepressant-induced violence, there is no data to support it.

      • Could you link to that study?
        In terms of correlating violence with anything at all – I’ve seen people attribute the decrease in violent crime to everything from global warming to lead pollution. In the same time the link between suicides and “paradoxical effects” and anti-depressants is quite clear. There is no reason to suggest that “depressed” people are more prone to violence either.

    • Fiachra,

      I hear of a lot of reports of bad reactions to psychotropics that don’t seem to fit with what the clinical trial data shows. I suppose some of this is because the trials are run by the manufacturer, but find it hard to believe this is the whole story given the use of academic clinical sites that are audited by the FDA. I suspect that individual variation in response has something to do with it. And depending on individual values, a single effect may be perceived by some but not others as harmful.

      There does seem to be a strong tendency in the blog world, that if a person is taking a drug, anything bad that happens to them (or anything bad they do) is blamed on the drug. I’m pretty skeptical o that reasoning. I’m sure that some people have bad reactions to these drugs (that seems very clear), but the idea that someone completely lacking violent tendencies is turned into a violent psychopath by a week’s treatment with an SSRI strains my credulity.

      I am glad you are doing better. I have had some rough years myself in the past, and am doing better as well.

  3. Can someone please refer me to clinical studies about the dangers and difficulties of Paxil withdrawal syndrome?…. Especially withdrawing cold turkey. I am particularly interested in instances where the withdrawal syndrome was misdiagnosed as a new major disorder instead of being recognized for what it was.

    Thank you!

  4. I agree wit bpd’s comments about Major Depression. Not only have studies repeatedly indicated that in adolescents, anti-depressants do not appear to be effective, but the diagnosis has to be questioned for it’s validity. In treating around 4000 adolescents and young adults over a 30 year period, I did not see anyone who fit well into this diagnosis. In general with both younger and older populations, the more one gets to know someone, the less the diagnosis of Major Depression makes sense. The DSM has kept loosening the criteria so now one could fit almost any person with some depressed mood into the diagnosis, but this just decreases any validity this diagnosis may have.
    In psychiatry, it is fairly easy to structure an interview to elicit one’s favourite diagnosis just by asking certain questions and limiting one’s exploration of a person’s true emotional experience. I know what to ask and how to phrase the questions to elicit a diagnosis of Major Depression, Bipolar Disorder or ADHD in just about any distressed person.
    It is crucial that adolescents with emotional struggles need proper support and therapy. The evolving adolescent brain will be impaired by the use of medication. The push to medicate adolescents and children has to stop.

    • True Dr. Hoffman, but I’d say that this same observation applies to almost any body of evidence. One can look at the data for almost any healthcare intervention, that regarding global warming, or that regarding the health impacts of GMOs, and by subtle decisions regarding how to weight various studies and the reliability of their results, support almost any preconceived position.

      In general, diagnoses serve to emphasize the common aspects of human experience, whether psychological or physiological, and to organize and suggest common approaches to problems that have shared aspects. I agree that they should not be used in a simplistic way to cubbyhole human experiences or to gloss over individual needs.

      I’m also aware that many people on this thread have had bad experiences with psychotropics. With children in particular, we know these drugs carry a lot of risk. But I am not aware of any objective evidence that “The evolving adolescent brain will be impaired by the use of medication. ” Rather it seems to me that the use of medication is an issue that should be addressed on an individual basis, taking into account the specific needs and values of the client.

      • John,

        As it related to the topic of this post, I am responding to your comment:

        ” With children in particular, we know these drugs carry a lot of risk.** But I am not aware of any objective evidence that “The evolving adolescent brain will be impaired by the use of medication. ”** Rather it seems to me that the use of medication is an issue that should be addressed on an individual basis, taking into account the specific needs and values of the client.”

        The reasoning you display here reflects the impact of RCTs on clinical practice guidelines, that has profoundly changed the role of a physician. Relying on the information produced by a flawed process that favors guild interests of both pharma and psychiatry, many doctors still contend that IF an adverse effect was not brought to light by a RCT, well, then it must not exist. This is one essential point of Dr. Healy’s post: Paxil study 329, is but one example of the risk a doctor is taking by relying on RCTs as a *gold standard* for clinical practice guidelines. Paxil was neither safe nor effective– based on the raw data obtained in this study– yet, here we are , 10 years after the black box warning finally appeared on drugs in this class, failing to take proper notice of the implications of relying on RCT style *objective evidence* to guide prescribing practices of psychotropic drugs for children and adolescents. This is mind boggling.

        There are standards that definitely should impact the attitude of doctors who are tempted to prescribe psych drugs for kids. My old school nursing/medical training guided me to study the developing brain for evidence of vulnerability and potential adverse effects of drugs that act directly on neurotransmitter systems and neuronal signaling mechanisms. I started with a medical text on the topic. James C.Harris, Director of Developmental Neuropsychiatry, Professor of Psychiatry and Behavioral Sciences, Pediatrics, and Mental Hygiene- Johns Hopkins University School of Medicine, is the author of a 2 volume text: Developmental Neuropsychiatry- Fundamentals”. First published in 1995. Dr. Harris states in the preface that information in this 2 volume work is presented to acquaint the reader with the material and is not intended to be an exhaustive review.

        No doubting that the prospect of tinkering with neurotransmitter systems in the developing brains of children and adolescents via psychotropic drugs is guided by works, such as this text,– but, in my opinion, there can be no denying that to do so is unethical.

        Here is my reasoning. There has been no substantiation for labeling behavior, emotional states and mental functioning with a diagnosis, calling any of these symptoms, as disease or a disorder. In contrast, for example, where there is a quantifiable means for diagnosing a disease, such as rheumatic fever- the careful calculations needed for prescribing a drug proven effective in eradicating Beta- hemolytic stop bacteria – to children is a clear example of addressing the use of medication on an individual level. What justification can be given for the off label prescribing of brain altering drugs ? Zero. Experimenting to the scale this practice has developed is also, IMO, illegal.

        Though it is beyond me how the practice of prescribing psychotropic drugs to kids began- meaning that the knowledge and expertise of a medical doctor seems to preclude this from having ever become an option. Rather, either ignorance of the intricacies of brain development, or willful denial of the significance of *what is not known* , has been the foundation of a practice that is brain disabling and wrought with serious physiological adverse effects as well –; this practice continues and is proliferating, with little to no regard shown by the medical community.

        I really don’t think that it is necessary to conduct in depth study of the developing brain, to question the prescribing of brain altering drugs to kids. Common sense suffices here. What has become a better for debate and endless intellectual speculation really seems more the product of brain washing a profession into relying on RCT evidence– . In Pharmagheddon, David Healy says that doctors are hooked on the crack pipe of RCT evidence– And it does appear to be an affliction that has caused the profession to behave in very serious destructive ways–. So long as these bogus clinical guidelines hold up as a defense for doctor being sued for careless prescribing habits resulting in injury or death– well, what is the hurry to change the view that until the objective evidence of harm is proven in a study– a RCT, no less, no need to heed a warning.

        ~Katie

  5. A nice initiative but I doubt it will make an impact. I think the key thing here is the money interest which will make sure this never makes it to the mainstream. It’s no about the science it’s about the power system, which is not interested in the truth if it hurts profits.