Like Footprints in the Sand

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An amazing letter was sent to the president of the American Psychiatric Association (APA) on August 1, 2016 by no less than sixteen well known medical and psychological professionals from around the globe. They are attempting to have an article published in a 2004 issue of the American Journal of Psychiatry retracted. Their concern was that a recent analysis of that study found “gross misrepresentations” made in the article with regard to use of citalopram (Celexa) in treating child and adolescent depression. As of the beginning of December of 2016, the original journal article is still available; nor does there seem to have been any response to the letter requesting the retraction. Perhaps the APA hopes that if they simply ignore the issue, it will just go away.

The article was ghostwritten by agents of the manufacturer and seriously misrepresented both the effectiveness and the safety of citalopram in treating child and adolescent depression.

The letter was addressed to Dr. Maria Oquendo, the 2016 President of the APA. The coauthors of the letter expressed concerns with the “gross misrepresentations” made within the 2004 article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents.”

Since the publication of the analysis alleging the problems with the 2004 Celexa article, there were three different attempts to have it retracted. In response to a May 9, 2016 letter, the current editor for the American Journal of Psychiatry refused to retract the original study. Two other attempts, one to the former editor of the American Journal of Psychiatry who accepted the article, received no response. Given the failure of the American Journal of Psychiatry to retract the article, the letter’s authors are concerned that children and adolescents are put at risk of unnecessary harm because well-intentioned physicians who continue to prescribe citalopram to children and adolescents are being misled.

The 2004 citalopram study said it provided evidence that “citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents.” It was said to be superior to placebo and the adverse events were mild.

In conclusion, citalopram treatment significantly improved depressive symptoms compared with placebo within 1 week in this population of children and adolescents. No serious adverse events were reported, and the rate of discontinuation due to adverse events among citalopram-treated patients was comparable to that of placebo. These findings further support the use of citalopram in children and adolescents suffering from major depression.

Yet there have been a series of lawsuits against Forest Laboratories, the manufacturer of Celexa, because of its serious side effects; and for Forrest’s failure to warn about the risks when using Celexa and other SSRIs. Drugwatch noted that Celexa is the best-selling antidepressant in 13 countries. Yet it has been linked to several congenital birth defects as well as autism. FindLaw noted evidence that Celexa and other antidepressants have been linked to an increased risk of suicidal behavior in patients under the age of 25.

Forest Laboratories also pleaded guilty in a 2010 criminal case for misbranding Celexa for a use not approved by the FDA. “According to the Department of Justice, Forest Pharmaceuticals had illegally promoted Celexa for the treatment of depression in children and adolescents. The company also pleaded guilty to obstructing justice and distributing an unapproved drug.” Forest Pharmaceuticals was fined $150 million.

A class action law suit, Celexa and Lexapro Marketing and Sales Practice Litigation, was brought by plaintiffs who alleged that Forest Laboratories misrepresented the safety and efficacy of Celexa and Lexapro when marketing the drugs for off-label pediatric use. Over 63,000 documents from Forest were deposited in a database maintained by the plaintiff’s attorneys. Jureidini, Amsterdam and McHenry reviewed 750 internal documents from this database in their 2016 article for the International Journal of Risk & Safety in Medicine.

They found that the published article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” contained efficacy and safety data that was inconsistent with the protocol criteria. Although the published article concluded citalopram was safe and significantly more efficacious than placebo for children and adolescents, the outcome measures “showed no statistically significant differences between citalopram and placebo.”

Unreported procedural deviations contributed to the claimed statistical significance of the primary outcome and negative secondary outcomes were not reported. Moreover, post hoc measures were introduced; and adverse events were misleadingly analyzed. The Wagner et al. citalopram study failed to mention five citalopram-treated subjects who discontinued treatment due to hypomania, agitation, or akathisia. “None of these potentially dangerous states of over-arousal occurred with placebo.” There were also many more adverse gastrointestinal events for citalopram than placebo. Yet the final report grouped the data in a way that masked the evidence for potential gastrointestinal intolerance.

In conclusion, corporate mischaracterisation of clinical trial results is of concern in psychiatry where outcome measures are more subjective and easily manipulated. Because few industry-sponsored studies gain public scrutiny and even fewer are ever formally retracted, it is important to make these articles transparent to correct the scientific record. It is furthermore imperative to inform the medical community of mischaracterized data that could lead to potential harm to children and adolescents who are vulnerable to the effects of medication on the growing brain and may increase suicidal thinking and behaviour.

STAT News reported the retraction request comes after years of controversy over the extent to which some drug makers massaged clinical studies to broaden their medicines’ market. Four years ago, GlaxoSmithKline paid $3 billion to settle civil and criminal charges of “preparing, publishing, and distributing a misleading journal article” about the use Paxil with children and adolescents. “The pill had not been approved for that use and the study cited by federal authorities had been ghostwritten.” David Healy, John Nardo, and Jon Jureidini, three of the sixteen individuals who submitted the letter to the APA requesting that the 2004 citalopram study be retracted, have been actively involved in critiquing the misrepresentation of Study 329 and attempting to get it retracted as well. See a series of articles Healy has written on this issue here, in the Mad in America archives.

After a running a gauntlet of reviews, Le Noury et al. were able to successfully publish a reanalysis of Study 329 in the British Medical Journal. But getting there wasn’t easy, see: “Restoring Study 329: Letter to BMJ” and “The Troubled Life of Study 329: Consequences of Failure to Retract.” However, the original article, “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial,” was never retracted by Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

Hmmm. Perhaps my opening comment that the APA is hoping the request to withdraw the 2004 citlopram article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” wasn’t all that smarmy. They could be hoping that it will just fade away like footprints in the sand.


Where There’s Smoke …

As much as 4 ½ years before the publication of the DSM-5, there was growing public criticism of the American Psychiatric Association (APA) and the process they used to develop it. The amazing thing about this criticism is that it was from within the ranks of psychiatry itself … by psychiatrists who had been in charge of previous revisions of the DSM.

In a 2008 article, Benedict Carey of the New York Times pointed out the importance of the DSM as a “medical guidebook and a cultural institution.” It is used to help doctors make diagnoses and to provide diagnostic codes to insurance companies. The National Institute of Mental Health made the use of DSM criteria a requirement for funding research. But for the first time, the APA required its DSM contributors to sign a nondisclosure agreement.

Research psychiatrist Robert Spitzer said that when he first heard about the agreement, he went “bonkers.” Spitzer said: “Transparency is necessary if the document is to have credibility, and, in time, you’re going to have people complaining all over the place that they didn’t have the opportunity to challenge anything.”

Robert Spitzer, the chair of the “landmark” third edition of the DSM, has been hailed as the rescuer or savior of psychiatry. Allen Frances, the chair of the 4th edition of the DSM said in his book, Saving Normal, that Spitzer was a rare man. “Without Robert Spitzer, psychiatry might have become increasingly irrelevant.” Even critics of modern psychiatric diagnosis, such the authors of the book Mad Science, acknowledge Spitzer’s importance to psychiatry: “Robert Spitzer was a most unlikely rescuer of American psychiatry.”

On June 26, 2009, Frances published an article in the Psychiatric Times where he identified what he saw a grave problems with the DSM-5. He also was critical of the lack of transparency. Pointing to his own efforts with the DSM-IV, he said their goal had been to ensure that everyone would understand what they were doing and how they were going about it. “There was explicit accountability for decision making on all changes.” He cautioned against the stated ambition to effect a “paradigm shift” in psychiatric diagnosis with the DSM-5.

So long as psychiatric diagnosis is stuck at its current descriptive level, there is little to be gained and much to be lost in frequently and arbitrarily changing the system. Descriptive diagnosis should remain fairly stable until, disorder by disorder, we gradually attain a more fundamental and explanatory understanding of causality.

Frances specified his concerns with the DSM-5 process, which included the following: 1) there was no scientific basis to justify a paradigm shift in psychiatric diagnosis at this time; 2) there was a failure to provide clear methodological guidelines on the level of empirical support for the changes; 3) there was a failure to be open to wide scrutiny and useful criticism; 4) there was a failure to set and meet clear timelines; there was a likelihood that time pressure would lead to an unconsidered rush on last-minute decisions.

The members of the APA working on the DSM-5, including the DSM-5 Chair, David Kupfer, responded APA to Frances on July 1, 2009. They suggested that both Spitzer and Frances were repeating “factual errors and assumptions” about the development of the DSM-5. After their refutation of the concerns expressed by Frances, they stated:

Both Dr. Frances and Dr. Spitzer have more than a personal “pride of authorship” interest in preserving the DSM-IV and its related case book and study products. Both continue to receive royalties on DSM-IV associated products. The fact that Dr. Frances was informed at the APA Annual Meeting last month that subsequent editions of his DSM-IV associated products would cease when the new edition is finalized, should be considered when evaluating his critique and its timing.

Robert Spitzer responded to the criticisms raised about Allen Frances and himself on July 2, 2009. Spitzer noted how the DSM-5 debate had taken an ugly turn, by suggesting that he and Frances were critiquing the DSM for financial reasons. He limited his comments to what he saw as the core issue of transparency. After raising a series of questions with regard to the opaqueness and “empty rhetoric” on the DSM-5 as the most open and inclusive DSM ever, Spitzer saw two possible reasons for the lack of transparency. First, the answers to his questions were known, but for some reason, the DSM leadership was withholding it; perhaps to shield themselves from criticisms. A second possibility was that the DSM-5 leadership didn’t know the answers to his questions. “Given their plan to publish DSM-V in May 2012, if the second possibility is the case, it is inconceivable that this publication deadline could realistically be met. “

Both Spitzer and Frances continued their challenges to the process of review and approval of the DSM-5 by the APA and gained more support and even some victories. You can also read a more detailed description of the dispute here. The publication of the DSM-5 was delayed until May of 2013, but the controversy merely grew. Allen Frances became one of the most vocal critics of the DSM-5, with multiple blogs and articles looking at the problems and concerns. He’s even written two books, Saving Normal and Essentials of Psychiatric Diagnosis as a result of this controversy. You can scroll through some of his articles on the Huffington Post for starters.

Oh and with regard to the veiled accusation of Spitzer and Frances criticizing the DSM-5 for financial reasons, David Kupfer, Chair of the DSM-5 Task Force, has been outed for failing to report financial interests in Adaptive Testing Technologies, a company that designs tests and implements large scale adaptive testing systems for mental health assessment. After an investigation, the APA said (Letter-to-Assembly-20140114.pdf; now removed from the APA website): “Dr. Kupfer should have disclosed to APA his interest in PAI in 2012.” However, it did not find that his interest in PAI had any influence on DSM-5’s inclusion of dimensional measures for further study in Section 3. One blogger, 1 Boring Old Man said:

It seems like Dr. Kupfer et al. are pursuing a strategy of only acknowledging this particular Conflict of Interest when forced, as in the situation with JAMA Psychiatry, and avoiding talking about it otherwise – mirrored so far by the APA President and Board of Trustees.



Psychiatry Has No Clothes

On April 29th of 2013, there was an astounding blog post by Thomas Insel, the Director of the National Institute of Mental Health (NIMH). He said that although the DSM-5 was due to be released in a few weeks, the NIMH would be “re-orienting its research away from DSM categories.” He noted that while the DSM has been referred to as a “Bible” for the field of mental health, “It is, at best, a dictionary, creating a set of labels and defining each.” Did you get that? The Director of the NIMH said the DSM was a “dictionary” that created “labels.” It was not, then functioning adequately, in his opinion, as its title suggests: as a Diagnostic and Statistical Manual of Mental Disorders! (emphasis added)

Insel said its strength had been “reliability”, meaning that it provided a way for clinicians to use the same terms in the same way. Its weakness was that it lacked validity. DSM diagnoses are based upon a consensus about clusters of symptoms and not any objective laboratory measure. “In the rest of medicine, that would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever.”

Insel was not using “reliability” in a statistical sense. In “The Myth of the Reliability of DSM,” Stuart Kirk and Herb Kutchins demonstrated conclusively that the DSM-III and DSM-IIIR were not statistically reliable. In fact, using the same statistic that Robert Spitzer used to justify the major changes to the DSM in the 1970s, they demonstrated that:

The reliability problem is much the same as it was 30 years ago [before the DSM-III]. Only now the current developers of the DSM-IV have de-emphasised the reliability problem and claim to be scientifically solving other problems.

Unfortunately, the tables in Figures 1 and 2 have been removed from the online version of their article. But the tables are still available in the original article found in the Journal of Mind and Behavior, 15 (1&2), 1994, p. 71-86. These tables plainly showed how the DSM statistical reliability was not what it was claimed to be. The Selling of the DSM (1992) by Stuart Kirk and Herb Kutchins has the tables. And there is a graphic comparison of the data within Mad Science (2013) by Stuart Kirk, Tomi Gomory, and David Cohen.

Insel went on in his blog to say that the NIMH will be supporting research projects that “look across current categories” or sub-divide them in order to begin to develop a better system. “We are committed to new and better treatments, but we feel this will only happen by developing a more precise diagnostic system.” In order to work towards that goal, the NIMH launched the Research Domain Criteria (RDoC). RDoC is only a research framework for now; a decade-long project that is just beginning. You can learn more about RDoC here (on the NIMH website).

Robert Whitaker, author of Anatomy of an Epidemic, said in a March 2014 interview that Insel stating that the DSM lacked validity was an acknowledgement the “disease model” has failed as a basis for making psychiatric diagnoses.

When Insel states that the disorders haven’t been validated, he is stating that the entire edifice that modern psychiatry is built upon is flawed, and unsupported by science. That is like the King of Psychiatry saying that the discipline has no clothes. If the public loses faith in the DSM and comes to see it as unscientific, then psychiatry has a real credibility problem on its hands.

Two weeks later on May 13, 2013, a joint press release was made by Thomas Insel and Jeffrey Liebermann, the President-elect of the American Psychiatric Association (APA). They said that the NIMH and the APA had a shared interest to ensure that patients and healthcare providers had “the best available tools and information” to identify and treat mental health issues.

Today, the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders. . . . The National Institute of Mental Health (NIMH) has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states: “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

The DSM and RDoC were said to be complementary, not competing frameworks. As research findings emerge from RDoC, they may be incorporated into future DSM revisions. “But this is a long-term undertaking. It will take years to fulfill the promise that this research effort represents for transforming the diagnosis and treatment of mental disorders.”

Saul Levine, the CEO and Medical Director of the APA said on May 5, 2014 that the DSM and the RDoC will “begin to come together” as the research from NIMH is included into the way they diagnose mental illness. They know that mental illness and substance use disorders are a bio-psycho-social illness. “We work very well together with NIMH. And I think that the whole field is looking to the science coming out of NIMH to include it as a way to help get better treatment for patients in this country.”

So the APA and NIMH affirm they are working towards the same goals as complementary research frameworks. Someday the research findings of RDoC may even be included into the DSM. But until then, the NIMH will have to continue to “ooh and aah” at the APA’s DSM and ignore the nay-sayers crying: “Look at the DSM; look at the DSM!”

Does it seem that psychiatry is trying to promote an unreliable, invalid—perhaps invisible—system of diagnosis?

Also see my blog post, “Psychiatry’s Mythical Phoenix.”