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The Op-Ed: Antidepressants & Controversial Studies


Several years ago, the Black Box warnings that were added to antidepressants over suicidal thoughts and behaviors for youngsters caused a backlash, as some suggested the language had pushed physicians and parents to avoid usage when the medications could have done some good. The debate may have slipped from view, but never really ended. A pair of papers published last year, in fact, renewed the controversy, and Glen Spielmans, an associate professor of psychology at Metropolitan State University, recounts why the issue remains fraught with challenges and a recent spat that erupted when an effort was made to critique the papers.

Antidepressants can cause suicidality – suicidal thoughts and behaviors – in children and adolescents. This message has been widely disseminated since October 2004, when the FDA placed a Black Box warning on such medications. The warning was based on findings from placebo-controlled trials, in which kids taking antidepressants had an elevated rate of suicidal thoughts and behaviors (see this). But research led by Dr. Robert Gibbons, professor of biostatistics at the University of Chicago, suggests that this warning is counterproductive, scaring parents and kids away from getting safe and effective antidepressant treatment.

Gibbons was the main author on two papers published in 2012 in psychiatry’s premier journal, Archives of General Psychiatry (which was changed to JAMA Psychiatry last month). One paper examined the potential association between antidepressants and suicidality and the other focused on the efficacy of antidepressants (read here and here). They analyzed data from placebo-controlled trials in youth, adults and in the elderly. Two important conclusions drawn by Gibbons and team: Antidepressants do not actually increase suicidality in youth and are more effective than previously believed for kids. Their findings are based on re-analysis of data from selected placebo-controlled trials which date back several years. Gibbons and others explained the importance of these findings in various mainstream and medical media.

For instance, in a Medscape article, an academic psychiatrist opined in support of the findings: “The black box warning might have prevented the medically appropriate use of antidepressants in teenagers. I am very happy to see this study come out.” The same psychiatrist added in the Lancet that the FDA warning “may have done more harm than good” (look here).

Making sure to weigh in on the Black Box in one of their 2012 papers, Gibbons and team wrote that “these findings should also favor reconsideration of the risk-benefit equation that led to the black box warning for suicidal thinking and antidepressants in children.”

Omitting The Bad News
Yet the two papers only analyzed a small slice of relevant data. In fact, the youth data came from only four studies, all of which used Prozac. But there are at least 15 placebo-controlled studies of eight antidepressants for the treatment of depression in youth (see this).

Gibbons et. al claimed to use data from “all sponsor-conducted randomized controlled trials of fluoxetine (Prozac) and venlafaxine (Effexor).” However, an inspection of the abstracts of their two 2012 papers reveals that no data were included from Effexor studies in youth. Yet a controlled study of Effexor in youth found no efficacy and increased risk of suicidality (look here). Though this post is focused on children and adolescents, it’s worth mentioning that Gibbons et al. also did not include data from a geriatric study that showed no efficacy for either Prozac or Effexor (read this). Omitting negative studies leads to an overly rosy picture of antidepressant efficacy.

In an analysis that combines data across several studies, researchers should provide a list of included studies for the sake of transparency; anyone with a critical eye would want to know where the data came from. The list of included studies in the papers doesn’t list published studies that one can obtain from the published, peer reviewed literature. Rather, proprietary names such as LYAQ and 016 are used instead. Good luck tracking down data from these studies; a few colleagues and I spent hours trying to obtain information online and could not find relevant information for most of these trials.

I eventually learned more about Prozac youth study LYAQ (here it is). Turns out that 1) 99 percent of participants had an ADHD diagnosis, 2) less than half of participants had a diagnosis of major depressive disorder, and 3) duration of treatment with Prozac vs. placebo was about three weeks – only half the six-week minimum stipulated by Gibbons. None of this essential information is provided in the papers. A small bit of inappropriate data might not impact the overall findings but LYAQ included 127 kids taking Prozac, 32 percent of the 393 youth across all four studies who took the drug. How can we trust the conclusions when data from nearly a third of Prozac participants should have been excluded?

Also excluded was a small adolescent trial of Prozac which appears to have found minimal benefit for the drug over placebo. This exclusion was more understandable since depression was measured differently than in other studies, but it still biases their findings. Moreover, there was no mention that the studies included found the lowest placebo response rate among antidepressant studies in youth, making Prozac shine all the brighter (see here). While the placebo response rate was low, it is higher than the 5.7 percent rate claimed by Gibbons et al. My colleagues and I carefully examined these studies and found nothing suggesting a single-digit response rate.

In sum, only four antidepressant trials on kids were included, all of which used Prozac – one of which (LYAQ) was obviously inappropriate – plus a Prozac study which showed little benefit was excluded. Further, negative data regarding Effexor was not included. Data from other antidepressant trials in kids, the vast majority of which found little to no benefit were also not included (look here). To top it off, studies were selected with the lowest placebo response rate and then, somehow, the authors calculated an even lower placebo response rate than described in the previously published versions of the studies. No wonder there were positive results.

Suicidality, Defined
Gibbons et al. defined suicidality as a score on a single item from a depression rating scale rather than actual suicide-related events (e.g., cutting wrists, telling study personnel of serious intent to kill oneself). The accuracy of these items in detecting actual suicidality is unproven. Prior research (read here) using actual reports of suicide-related events in all antidepressant trials (not just Prozac) led to the FDA Black Box warning. Yet Gibbons et al. decided that rating scale items not intended as in-depth measures of suicide risk in studies not designed to assess suicidality made for a reasonable assessment of what they call “suicide risk.” They also collected information on suicide-related adverse events reported to study personnel but did not report how the rate of these events compared for drug versus placebo. Two senior FDA officials have said that relying on rating scales to assess suicidality is ineffective. More details can be seen here.

Response To Critics
Along with three colleagues (Drs. Jon Jureidini, David Healy and Rob Purssey), I wrote a letter to the editor expressing the above concerns along with a few more. Our letter, and another critical letter from Dr. Bernard Carroll, appeared in the January 2013 issue of JAMA Psychiatry along with Gibbons and team’s responses. Suffice to say that the concerns raised above were not addressed sufficiently. Their response was a non-response.

Below are just a couple of the many points we made and the counterarguments provided:
1. Given that less than half of participants had a diagnosis of major depressive disorder, LYAQ should not have been included in their analysis.
Counterpoint from Gibbons et al: 81 percent of participants had a depressive disorder.
Rejoinder: Actually, 45.7 percent of participants had a diagnosis of major depressive disorder. The 2012 papers clearly state that they were an examination of antidepressant trials in “major depressive disorder.” The authors must also be including participants with diagnoses such as dysthymia and mood disorder not otherwise specified – these are not the same thing as “major depressive disorder.”

2. Effexor has no evidence of efficacy among depressed youth. Failing to include Effexor data paints an unduly optimistic picture of antidepressant efficacy among youth.
Counterpoint: Spielmans and colleagues cite an effect size of 0.14 for youth venlafaxine studies (minimal and non-statistically significant), based on a meta-analysis of endpoints without the benefit of complete longitudinal data as we used.

Rejoinder: The authors claim that their method of analyzing data is better than what has been done in the past. But there is no reason to suspect that by re-analyzing existing data, Effexor (or other antidepressants such as Paxil) would somehow become resoundingly effective for depression in children/adolescents.

A rundown of a) all the points we made along with b) the counterpoints from Gibbons et al and c) a response to their responses is available here.

Back to the Black Box
Gibbons has been discussing the evils of the Black Box warning for years (see The Los Angeles Times and WebMD, for instance) and he’s certainly entitled to his opinion. Yet in their response to our letter, Gibbons and team acknowledged their findings regarding Prozac do not necessarily generalize to other antidepressants; in other words, they are not commenting on the Black Box warning. But in one of the 2012 papers they wrote: “These findings should also favor reconsideration of the risk-benefit equation that led to the black box warning for suicidal thinking and antidepressants in children.” There is no logical way to reconcile those two statements.

Stifling Dissent
My team, Carroll, and Dr. Mickey Nardo all sent letters to the editor regarding the Gibbons papers. All letters cleared the peer review process in April 2012. Despite no concerns being raised by reviewers, the editor offered to publish our letters in a place best described as Scientific Purgatory. The letters would have been published in an online repository hidden behind the journal’s paywall and not indexed in any scientific database such as Medline. In other words, they would not be part of the official scientific record.

Science is meant to be self-correcting; flaws identified by readers should be noted in the official scientific record, not swept under a rug. None of us accepted the editor’s offer, and he did not change his decision. Nardo posted his letter to the journal on his own blog (see here).

However, two additional research teams (Sonia Swanson et al. and Sparks & Duncan) accepted the offer, with their comments appearing online in June and July 2012. One concern noted that there was a trend toward increased suicide rating scale scores for kids taking antidepressants vs. placebo. Gibbons and team responded in October 2012, without a good explanation for how a trend toward increased suicide rating scale scores for youth reconciles with their claim of no increased risk. A back and forth between Swanson’s team and Gibbons appeared in Medscape (story here).

Imagine my surprise when I received a voice mail in October 2012 indicating that my letter to the editor was being prepared for print publication after all. Dr. Carroll also was pleasantly surprised to receive a curt e-mail, though it had no explanation for the editor’s reversal (you can read the letters from Spielmans et and Carroll and the replies from Gibbons et al here and here). While we commend the journal for eventually publishing our critiques, this episode speaks to arbitrary and capricious editorial decision making. To this day, the additional critiques offered by Swanson et al. and Sparks & Duncan still reside in Scientific Purgatory.

There are lessons to learn from this episode. Major scientific and medical journals like JAMA Psychiatry have a bully pulpit in policy debates like the Black Bbox warning on antidepressants. When these journals publish such articles, they have a clear responsibility to correct any errors on the record. Peer review should not end when an article is accepted for publication (read this).

This is more than an academic debate. Thousands of psychiatrists and other prescribers have read the 2012 papers. Relying on the reputation of the journal, many will have been convinced that the FDA Black Box warning was based on thin data whereas the authors had the real answers. After all, they used “complete longitudinal person-level data from a large set of published and unpublished studies.” Sounds impressive until you examine what actually happened. This is the type of study that can misinform physicians, patients and policymakers alike.

Let’s conclude with a simple thought experiment: Suppose a paper with similarly obvious issues reached opposite conclusions (antidepressants are ineffective and linked to increased suicidality risk in youth). Would JAMA Psychiatry have published the paper and/or tried to stifle its critics? Just wondering.

Jump to comments



  1. Excellent,informing piece. Thank you.

  2. It is bad enough that the two Gibbons papers were published without competent peer review. It is bad enough that well informed critics were given the runaround by the editor of JAMA Psychiatry. And it is deplorable that the responses by Gibbons et al to their critics were so evasive. Dr. Spielmans is right to say that inclusion of Lilly study LYAQ outright invalidates the aggregate analyses. The rejoinder by Gibbons et al about LYAQ is a calculated prevarication. They did the same thing in trying to counter the charge of computational error. They invoked voodoo mathematics and hand waving to explain away major errors in some of their calculations of Number Needed to Treat (NNT). Unfortunately for them, this smoke and mirrors tactic overlooked the fact that we did agree with most of their NNT calculations. Their lame attempt does not pass the straight face test.

    I urge the authors and the editor to retract these deeply flawed articles.

  3. “Let’s conclude with a simple thought experiment: Suppose a paper with similarly obvious issues reached opposite conclusions (antidepressants are ineffective and linked to increased suicidality risk in youth). Would JAMA Psychiatry have published the paper and/or tried to stifle its critics? Just wondering.”

    I would say probably not. The literature contains a vast array of articles reaching exactly such conclusions, many of which were published in JAMA or in JAMA Psychiatry (or its predecessor, the Archives of General Psychiatry).

    I went to the JAMA Psychiatry website to read Dr. Gibbon’s response to the criticisms laid out here. But for all my efforts, Dr. Speilman’s critique is available to non-subscribers, but I was not able to gain access to the full text of Dr. Gibbon’s response.

    Let’s do a simple thought experiment: What sort of conspiracy theories would be woven if the opposite were true?

    So lets be intellectually honest, and not employ silly propaganda techniques like claiming that your point of view is being suppressed. Its bad science and generally unattractive behavior.

    I agree with Dr. Spielmann’s criticism of the lack of an explicit list of studies excluded from the meta analysis. Sadly, this criticism is not unique to Dr. Gibbon’s paper, but is also true of virtually every meta analysis that is published. Given the widespread use of the study selection process by pharmaceutical companies, industry critics, and others to slant the data to their pre-existing point of view, it would be good to see this sort of list included in every such study.

    Expand full comment
  4. As a Risperdal marketing executive once noted, “Money Drives Behavior.” The Journals depend on Big Pharma advertising dollars, and Gibbons’ entire career has been spent in service the the Drug Industry. ‘Nuff said.

  5. John2: I am happy to provide you a copy of Gibbons’ reply if you’d like. It’s also linked above (

    I was not talking about any grand conspiracy. I described my experience – and the experience of others – who tried to write dissenting letters which pointed to problems in the Gibbons papers, and were then told that their letters would be published behind a paywall and not indexed in Pubmed. Having a letter not published because it is irrelevant or incorrect – that’s fine. Having a letter not published because, as the editor put it, there was not enough space in the journal, that looks more like having one’s view suppressed. If there is space to publish studies with substantial flaws, there should be space for others to point out these flaws.

    At the end of my post, I speculated that a paper which reached different conclusions than the Gibbons papers would have been treated differently at the journal. I don’t think this is invoking a conspiracy; it’s hardly news that journals treat studies differently based on their findings and conclusions.

    My experience with meta-analysis or pooled analyses is that industry-sponsored papers are more prone to include data from unpublished, inaccessible datasets. This is likely because they have access to their own data whereas outsiders or industry critics generally do not. Providing a list of included studies that can be easily accessed by readers seems like a reasonable minimum standard.

    Expand full comment
  6. I believe that, in almost all cases of mass shootings, the shooter was clearly mentally disturbed. Probably many, if not most, of them were on some sort of medication.

    What sort of data exists regarding the likelihood of anti-depressants (or perhaps other) pharmaceutical products causing violent behavior? An example might be the subject of the following story:

  7. The public should be very grateful to Drs Spielmans, Carroll, Jureidini, Healy, Purssey, Nardo, Sparks, Duncan, Swanson and a few other brave souls for sticking with it all these years to finally expose these bogus studies as the fraud that they are.

    I’d like to see the total hours they all put in at their own expense.

  8. “Dr. Gibbons has served as an expert witness for Wyeth Pharmaceuticals. Dr. Brown directs a suicide prevention program at University of South Florida that is funded by JDS Pharmaceuticals. Dr. Mann has received research support from GlaxoSmithKline and served as an adviser to Eli Lilly and Lundbeck. All other authors report no competing

    – COI disclosure from: Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents; Am J Psychiatry 2007; 164:1356–1363

  9. Science may be intended to be self-correcting but in reality this only happens when there is incontrovertible evidence of the correcting data, and even then there are doubters.

    The late Dr Howard Temin discovered the enzyme reverse transcriptase to explain how RNA could serve as a template to reverse synthesize DNA. This went against what was considered to be “established science”. Temin had doubters for some time until the science was self-corrected.

    Given that background of objective self-correction I highly doubt that black box warnings on suicidality will ever be removed. In fact I am not aware that FDA has ever removed a BBW in spite of evidence to the contrary. They are too risk averse.

  10. @OII You can get a Black Box Removed, Heck the same compound can even go OTC years later. Best lesson possible that statistics, science, medicine, and the real world impact of a drug must be balanced. I doubt the FDA would be so mindful today, and SSRIs and PPIs are pretty different. Prilosec 1995

  11. Agency guy, to be more precise you can’t get a CLASS EFFECT black box removed for an individual drug within the class. Thus if there is a class effect warning for all SSRI’S, even if you develop a new SSRI that shows no evidence of suicidality you still get the BB.

  12. Hats off to Dr. Spielmans et al for their pursuit of the truth in the face of industry-funded obfuscation and runaround. Let’s hope that the Obama Administration, in its so-critical quest into mental health and gun violence, will devote researh money to get at early warning signs of violence caused by the SSRI/SNRI antidepressants so that such awful incidents can be prevented. It is shameful enough to misinform the medical profession, but criminal to misinform a gullible public in this way.

  13. What is stiking to me is that Gibbons has been considerably involved in the pop media trying to debunk the suidality risks of SSRIs–ABC news, WashPost, etc. So this goes well beyond whatever is published in JAMA or Archives and appears to be a full throttle PR offensive.

    It is accompanied by the usual talking points re: FDA–regulations leading to “dangerous over-warning,” doing more harm than good, etc.

    I will not pretend to know what the truth is on this particular issue. But the science/ideology mush is pretty easy to spot because it has been so tediously repeated over the course of FDA history.

  14. Does anyone know for what cases Gibbons served as an “expert witness” for Wyeth?

  15. Thanks for publishing this important digest of how a falsehood marches halfway around the world while the truth is still getting its pants on — or in this case, the truth fights with a supposedly scientific journal to have a letter to the editor printed in an accessible format. The campaign to discredit the Black Box Warning, the active media commentary of a biostatician and non-clinician with no experience dealing with drug side-effects, the research grants seeking new ways to calculate suicidality, all of it seems agenda-driven, reckless, nonscientific, conveniently profitable and arrogant. Just try to find another federal safety warning that is as routinely dismissed by influential clinicians and researchers as is the BBW. Dr. Spielmans and colleagues get a lot of credit for doing the time consuming work necessary to stem the impact of these papers. The problem is, a lot more clinicians will read about Dr. Gibbons’ two papers and see their coverage in mainstream health publications than will ever read this blog.

  16. Paul, I wonder if this most recent push against the BBW on antidepressants is out of fear? There have been so many inexpicable shootings in which the shooter was an unlikely candidate to have done so, and in at least some cases, the person was taking and/or just off one of the SSRIs.

    This “segment” of the industry is in the neighborhood of billions per year, while the loss or cutback of this tool of psychiatry would be a dent for that group as well.

    If so, it would be about time. Very excellent research shows that cognitive behavior therapy has much better results than that of the placebo effect caused by SSRIs, plus it’s cheaper. This is a long overdue national conversation that needs to happen. The book “Anatomy of an Epidemic”, by Robert Whitaker, lays out the stakes, and the harm done by the “pill model” of mental health care, clearly and cogently.

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