Seroxat: GSK’s ‘Thalidomide Moment’?….

I have long been calling the Seroxat scandal ‘the mental health thalidomide’… I even sub-headed this blog with ‘Seroxat the mental health thalidomide’, when I set it up 9 years ago…

In the following article, by academic Redmond O’ Hanlon, Redmond discusses the implications of GSK’s notorious Seroxat Study 329..

Redmond calls this ‘Psychiatry’s Thalidomide Moment’

I think it was GSK’s thalidomide moment..

Psychiatry has had its thalidomide moment regularly since its inception..

The scale of harm which psychiatry has caused for over a century now is colossal..

Seroxat caused death and destruction on a much larger scale than Thalidomide, and GSK’s 3 Billion dollar Fine (see whistleblower Greg Thorpe’s complaint to the Dept of Justice here) lists endless pages of harm to consumers from several drugs over decades..

GSK have their thalidomide moment regularly too, at least once a year it seems.. Myodil, Seroxat, Avandia, Pandemrix, Wellbutrin…

..they really do live up to their nick-name of ‘Global Serial Killers’..

Study 329: Psychiatry’s Thalidomide Moment, Part 2

Nobody has retracted or apologized for a study that was an academic disgrace—but a marketing coup for GSK—which may well have caused untold numbers of deaths, suicide attempts and irreversible anguish to myriad families. Can we stand idly by when we’re told that it “accurately reflects the honestly-held views of the clinical investigator authors who do not agree that the article is false, fraudulent or misleading.”? What is the current market value of the honestly-held views of people who tell lies?

I’d like to reflect on a few major aspects of Study 329 and the recent BMJ restoration study (RS) which raise fundamental ethical issues, and which pose some theoretical problems or raise other important issues which haven’t yet been scrutinized. And, by counterpointing Paxil against Thalidomide, I shall suggest that a seismic cultural shift has made studies like Keller’s almost inevitable.

1. Ethics and Academic Integrity

Study 329 forces us to confront the ethical question once again, before it’s too late, and question the claim that the investigators were chosen only for their expertise, their interest in the subject and their capacity to recruit volunteers.  Might they not have been in the pay of GSK, or have been friends, ex-students or colleagues of people like Biederman, Keller, Krystal or Nemeroff? Or chosen for their commitment to drug solutions, regardless of awkward research findings, in line with the FDA which wrote at the time that there may be negative findings even in trials of drugs they know really work? Even at the initial stages, then, there was plenty of room for manoeuvre, allowing GSK and its (paid?) investigators to take advantage of a fuzzy diagnostic category, to cherry-pick the subjects most likely to produce favourable outcomes and to discount the gravity or relative severity of an adverse event if it suited their purposes.

The sociopathic lack of remorse and moral consciousness shown by GSK, Keller, et al., became most shockingly apparent early on, in GSK’s serial re-writing and occlusion of troubling data — designed to stop negative results leaking out to doctors, the public or their sales staff. In fact, a GSK internal memo showed that the company knew that their studies had failed to demonstrate efficacy since at least 1998; and in 2003 the MHRA revealed that GSK’s own studies showed that the drug actually trebles the risk of suicidal thoughts and behaviour in depressed children. Outside the Holocaust, I’ve never come across a more chilling, amoral or sociopathic memo than the one they sent out to senior management, clarifying their decision “to effectively manage the dissemination of these data in order to minimize any potential negative commercial impact…It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.”  In the same cynical vein, an email from a PR executive working for GSK said: “Originally we had planned to do extensive media relations surrounding this study until we actually viewed the results. Essentially the study did not really show it was effective in treating adolescent depression, which is not something we want to publicize.”

An important ethical barometer is the prevalence of authors’ conflicts of interest (COIs), though it is really a wider, cultural, problem, for a large majority of medical and science journals in the world have no COI policy. While we weren’t told about the authors’ COIs here, we now know those of Keller, Ryan, and of GSK employee Mc. Cafferty, whose affiliation was hidden. We know, for example, that Shelley Jofre sent emails to Dr. Ryan in 2002 asking questions about the safety of Paxil, whereupon this “independent” researcher forwarded them to GSK, asking for advice on how to respond to her! We know also, thanks to Peter Doshi, the extent to which Karen Wagner was beholden to BP. I have since followed up her case: it beggars belief.  Hunting down the COI hare of the other “authors” could bring to light some very damning evidence indeed.

The prevalence of ghostwriting is another disturbing example of ethical indifference: David Healy, who has monitored this phenomenon rigorously for years, estimates that up to 50% of apparently serious academic psychiatric studies are ghostwritten. Could this be a devious way of getting around the ban on off-label promotion?

The rampant, unethical ubiquity of ghost writing has sullied the reputation of numerous academics and their institutions in the U.S. Hannah Arendt’s reflection is apposite here: “When all are guilty, no one is; confessions of collective guilt are the best possible safeguard against the discovery of culprits, and the very magnitude of the crime the best excuse for doing nothing.” Here, however, we have no confession of collective guilt; not surprising, since guilt implies a minimal moral conscience, which was so rare here and among Chemie-Grünenthal’s (C-G) top brass in the thalidomide tragedy, some of whom had seen active service in the camps, and most of whom had impeccable Nazi credentials. This brings to mind those studies some years ago showing that a large proportion of industry CEOs could be classified as sociopaths: another indicator of a huge cultural shift. Are we now simply facing the inevitable consequences of rampant neo-liberal economics?

We could of course argue that this entire affair could be reduced to just one issue: is there any justification for ghost-written academic studies, especially when they have serious safety implications? If it is deemed to be professionally acceptable, then the “authors” of Study 329 have committed no sin at all: it’s just par for the course. After all, PLoS Medicine, which has been leading the charge against ghostwriting, found that only 13 of the top 50 medical schools in the U.S. have a policy that prohibits it.

At a 2011 U. Toronto conference on ghostwriting, Trudo Lemmens, a law professor, said that biomedical ghostwriting is a public health issue needing serious attention, since erroneous use of pharmaceuticals is a leading cause of hospitalization. Many studies, like Keller’s, contribute to that by hiding adverse events, negative data, and over-emphasizing benefits, so academics fronting such studies are responsible for any ensuing prescriptions and harms. Yet there seems to be no backing in law for those wanting to hold academics legally and professionally accountable: ghostwriting is perfectly legal, widely practiced yet officially considered unethical, so universities are nicely protected when they routinely protect shady researchers, who bring them prestige and large research grants. McGill, though, showed commendable rigour and oversight in the Sherwin/Wyeth case.

Doshi and Healy have no doubt that Study 329 was ghostwritten, but I’m not yet absolutely sure about this, though the circumstantial evidence is overwhelming. Keller’s recent letter defending his study and criticizing the RS does indicate that the “authors” were centrally involved at all stages of the study. Could they be forced to take an oath on this, as was Sally Laden? I’m still very unclear about which authors knew what, if anything: the much- compromised JAMA tried, unsuccessfully, to find this out when first offered the article. Keller’s slippery filmed statements and his facial language made me very suspicious indeed, as he repeatedly dodged interviewers with statements like: “I don’t remember matters like this…I never read such tables.”

However, let’s now suppose it wasn’t ghost written, then Keller has painted himself into an inescapable corner, since the only excuse he could proffer for producing scholarly work that drew conclusions contradicting the raw data was that it was, in fact, ghost written. Either that or they produced scholarship that would not have been accepted from an undergraduate, but was accepted by the editor of a prestigious journal who brushed aside THE JOURNAL’S OWN REVIEWERS’ DEEP RESERVATIONS about the study.  Why?

2. Pseudo-science, Lies, Damn Lies, and Statistics

Another ethical casualty of Study 329 was peer review, a protocol designed to guarantee the integrity, independence and rigour of published scholarship: JAMA followed the protocol strictly, and rejected the study, but JAACAP did not. How did it get away with so few official criticisms or sanctions? The story behind the editor’s ultimate acceptance of it could prove very incriminating, and throw up even more serious questions about academe’s failure to uphold minimal standards by publishing a labyrinth of lies, half-truths and lies by omission. The intellectual dishonesty displayed here by members of a prestigious Ivy League university is a bloody blot on the escutcheon of American academic integrity. Standards like this in very high places should not be tolerated by any academic community worth its salt.

The RS also highlighted an area which is rarely discussed: statistical analysis. We have become hung up on whether the results of a trial had statistical or clinical significance, but this study reminds us of the value of patient narratives, “merely anecdotal” reports and descriptive statistics, as did the thalidomide tragedy. Here, the commitment to descriptive statistics was abandoned, probably because they might have allowed non-specialists to make judgments and informed decisions, whereas more sophisticated techniques offered a smokescreen to hide behind for years, thus allowing billions to accrue. How many of us are sufficiently qualified to evaluate what the statisticians tell us, and how they tell it?  Unsurprisingly, GSK told us that they employed the best ones here: this may well have been the only true statement they uttered. It was in their interest to hire the top people, pay them a fortune and make it clear that, without making fools of themselves professionally, they should choose designs, protocols and methods of analysis likely to give the required positive results.

Jureidini’s team forces us to radically critique another untouchable: RCTs, whose status, integrity and even utility must now be thrown into question. Following Breggin, Cohen, Doshi, Harrow, Healy, Kirsch, Moncrieff, Timimi, Whitaker et al., we RCT sceptics now have much more precise ammunition to fight with. In their wake, can we continue to have faith in any previous RCTs and meta-analyses when so many negative trial results are never published and when fundamentals like blinding and adherence to protocols are so flagrantly flouted? Is this just the tip of a very large, murky and treacherous iceberg? After all, Study 329 was published in a top journal, yet deviated from the original protocols, added several new outcome measures, sometimes after un-blinding, and drew conclusions directly at odds with their own findings. In particular, I am deeply suspicious about its level of sustained adherence to blinding protocols.

Over the years, we have had many scandalous instances of unethical manipulation which allowed BP an easy ride. Keller et al. gave us an egregious example of this when they disbanded reliance on Hamilton, but never registered the change, blithely declaring that since the profession had moved beyond Ham-D between 1993 and 1998, they needed to look at other more appropriate measures! As we say in Dublin: ”Pull the other one, it has bells on it!” I know of no evidence that he was right, and their unseemly scratching around for scales, criteria and about 20 new secondary outcomes that might show Paxil in a more favourable light was sad, desperate, even comical.

In short, we’ve had many reasons to be extremely sceptical of RCTs and critical of the uses to which they have been put: Study 329, for example, was merely a super-lucrative advertisement for a dangerous, addictive drug with doubtful benefits and numerous toxic side-effects. (In 2002 over two million paediatric Paxil prescriptions were written in the USA alone, just in time to beat the patent deadline.) Now whereas the law, the FDA and blind faith in RCTs bought an awful lot of time for GSK to make many billions unimpeded in subsequent years, a modest number of academic articles and individual “anecdotal” reports from doctors between 1958 and 1961 stopped thalidomide in its tracks by 1962. They didn’t hang about too long in those days: one critic was scandalized that C-G knew for six whole weeks of the dangers posed by thalidomide!

The RS, then, may well deal a mortal blow to our naïve faith in academic integrity, our bedazzlement by RCTs, and to our easy acceptance of them as gold-standard benchmarks of truth and rigour. It should, at the very least, put them in their place as one potential, yet fallible, tool in the arsenal of psychiatry, but one that should never be allowed to usurp the centrality of the empathic, dialogic relationship between a singular patient and healer, nor the full story of individual suffering, which is obfuscated by algorithms and statistical averages.

On the other hand, the RS might also, paradoxically, provoke a more positive, nuanced view of RCTs, suggesting that some modicum of scientific respectability could be maintained, but NOT IN THE PRESENT VENAL CULTURE: Jureidini et al. have shown us what they might yield if carried out rigorously by top independent researchers putting in Herculean work for no financial gain: had their study appeared in 2003 many wasted billions and many, many lives might have been saved. But how often are we going to get such a highly qualified, deeply committed, hard-working group together in the present climate, with its routine financial inducements? Should we not, perhaps, use the thalidomide case to reconsider the value of strong, repeated “anecdotal” pointers, thus emphasizing individual stories of psychotropic drug use and the withdrawal therefrom? David Healy, Luke Montagu and James Davies have given us a very strong lead in this domain.

Another problem hovering over, but not addressed, by both studies is that of causality: in psychiatric and neuroscientific discourse there’s a lot of slippery semantic skating going on – “linked to,” “associated with,” ”implicated in,” “correlated with,” and the like, but rarely “caused by.” This is not always helpful, but it does bespeak an understandable and judicious reluctance to assign one cause to any outcome.  The Study 329 authors cleverly exploited this difficulty when they tried to minimize serious adverse effects related to treatment by declaring that “causality cannot be determined conclusively.” A single cause for any illness can rarely be proven conclusively – even in cancer, as a number of commentators have pointed out. Thalidomide, however, does appear to have been the sole cause of all those awful deformities; but even in a case like PKU, which is habitually deemed to have a purely genetic aetiology, the gene will not express itself if rigorous environmental controls are put in place – in this case, diet.

Now while it seems clear that judges, biomedical academics and psychiatrists have grossly underestimated antidepressants’ (ADs) contribution to suicidal behaviour, it is also possible to overstate the case by insisting that a given SSRI caused violent, murderous or suicidal behaviour, thus negating the potential impact of other confounding variables. Yet some, but not many judges, taking the advice of people like Peter Breggin and David Healy, have declared that an AD like Prozac had indeed induced a murder.  But, pace both of these great fighters, I’d suggest that legal sanctions would be far easier to obtain if we focussed not on a conclusive single cause for a violent act, but on the very high risk factors associated with a given SSRI and on the full personal and contextual story.

3. The Matter of Suicide

In the opening of The Myth of Sisyphus, Camus argued that suicide is the only serious philosophical question, but for many, suicidal ideation (SI) is a dangerous by-product of SSRI consumption; a serious adverse effect. And further, SI means different things to different researchers.  For some, it is a particular preoccupation with suicide, ranging from regular random thoughts, to more sustained and frequent thoughts of suicide. For others, however, SI includes suicidal gestures or behaviours such as the planning or rehearsing of the act, incomplete attempts, or more serious attempts designed to fail. Even the MedDRA confuses the issue by coding suicidal ideation OR self-harm OR attempted suicide as suicide events. The RS rightly criticizes Keller for using the term “emotional lability” to fudge the severity and differences in suicidal behaviours, but have they not also engaged in some fudging by lumping suicidal thinking and events under one heading, “suicide-related adverse events”?

There is too much fuzzy thinking here: surely logic and scientific rigour oblige us to clarify our terms and avoid assigning the same weight to SI and clear suicide attempts, since most people who have suicidal ideation do not go on to end their lives, even though it must be considered a (low?) risk factor for suicide? To put this in context, it was estimated that in 2008-9 over 8.3 million adults aged 18+ in the U.S. reported suicidal thoughts in the previous year, but of these, only one adult in 140, 60,000 people, actually took their own lives. SI does not usually mean that someone wants to die, but that s/he does have a desperate need to express her/his hopelessness, impotence, overwhelming pain or collapse of meaning. It may often be a natural strategy employed in a hopeless situation: an imaginative rehearsal or symbolic expression of entrapment in the reptilian freeze response; of the impossibility of fight, flight or social engagement, to put it in terms of Polyvagal Theory.

I’m suggesting, then, that we must beware of falling into the trap of dramatizing or pathologizing something that may be absolutely normal, even healthy, in certain circumstances: for example, if one is homeless, disadvantaged or marginalized, living in unbearable social conditions, or trying to deal with overwhelming loss or failure the lack of SI would surely be a highly dissociative move.

Pain, danger and thoughts of suicide often attend the birth-pangs of any major life transition or change in status, as it did for Tolstoy and J.S. Mill. (See James Davies’ fascinating book, The Importance of Suffering.) Camus’s Meursault normalizes suicide  by reminding us that everyone at some time has wanted to kill the one s/he loves: for adolescents needing to separate and carve out their own identity such thoughts are routine, healthy, and not necessarily caused by SSRIs. And for them SI can be one way of managing the maelstrom of hormonal turmoil, passionate intensity, emotional lability and high-risk behaviour attending the scary transition from childhood to adulthood. It may simply well be a way of saying that s/he sees no meaning in life and cannot go on this way any more, especially at a time of collapse in traditional values.

We need to remember, too, that modern adolescence, bereft of mentors, is a particularly fraught, unstable time, in which risky behaviour is far more common than in childhood or adulthood; one in which accidents are the main cause of death, followed by suicide, regardless of any SSRI consumption. (See Sarah-Jayne Blakemore’s research on risk-taking behaviour in adolescents.) For example, in one recent case it became clear that a vicious racism had fueled multiple murders in a local school. In another, a recent school killer’s notebooks showed that he was in a state of absolute despair because doctors had told him he was condemned to live with “a broken brain” for life.

However, well-documented adolescent suicide attempts do have to be taken very seriously, even though they may well be just last-ditch screams for help or understanding: after all, David Healy and others point out that for every eleven suicide attempts there’s one actual suicide.

I believe, then, that it is important to de-emphasize and downgrade SI since the term is used too loosely and can a have a positive valency. Why not confine the term solely to thoughts, and prioritize clear suicidal behaviours? And, taking into account the wider cultural framework, would it not make more sense for judges and researchers to focus on the individual contexts and narratives subtending acts of serious self-harm, clear suicide attempts and very uncharacteristic acts of violence? Drug are usually part of a much bigger story, which we neglect at our peril.  Why not, then, let the law get on with assessing the strength of the circumstantial evidence and decide whether a given drug is a major contributor to a suicide beyond any reasonable doubt?

4. Neo-liberal Culture

Martin Keller recently made the point that since nobody has been able to pin anything on the authors, there’s obviously nothing to apologize for. The terrible thing is that he’s right: they have merely acted in a way that is condoned by academic journals, the FDA and the universities; sanctioned by the psychiatric establishment and the wider culture which makes it so easy for negative findings to run for cover, since there is no firm regulatory obligation to report all the results from clinical trials. In this case, Brown is in the dock, but numerous U.S. academic establishment have been regularly shamed, even though a few of them, like Harvard, have had the courage and integrity to come clean in similar cases, so why not Brown, whose officials conveniently lost some vital incriminating data? (Precisely the same thing happened with a vital incriminating registered letter at the C-G thalidomide trial.) Harvard did take some nebulous action against Biederman et al., but only when the scale of the deceit had become too blatant to hide. It is quite shameful that most U.S. universities routinely offer no comment when the media or people like Senator Grassley ask the tough questions about questionable research or COIs. Indeed, Grassley has said that they seem incapable of monitoring the COIs of faculty. Like the all-powerful gun lobby that even Obama can do little to tame, Marcia Angell’s 800-lb. gorilla has run amok, and thumbs its nose with impunity at the helpless Sorcerer’s Apprentice. And at all of us who protest so loudly and so often. But is this enough? Do the times not demand more concrete, radical action?

Is Study 329, then, not just one more shocking example of the mercantile values and the druggy doxa that permeate our entire culture? Obama’s choice when appointing the new FDA director is a stark incarnation of just how bad things are. So, before we all get too righteous and complacent we mustn’t forget that JAACAP, GSK, Keller et al. are simply following the ethos of our culture in which ethics and transparency have been all but abandoned, even at the top. Earlier this year, Scott, Rucklidge and Mulder studied the adherence, from 2009-13, by the editors of the five leading psychiatric journals to their own pious protocols of oversight and integrity, concluding that “most trials were either not prospectively registered, changed POMs or the timeframes at some point after registration or changed participant numbers.” When such oversight is so loose at the top, to whom do we turn for safe, rigorous research and unbiased guidelines? Quis custodiet ipsos custodes when they countenance criminal acts?

The Study 329 affair, then, underscores the fact that there is strong, but implicit, cultural permission given to BP and amoral academics for their chicanery since trial periods are so short, and post-marketing surveillance so weak and random. Our modern blind-eye culture has no problem with FDA laxity, blatant academic corruption and an increasingly perfunctory oversight by Congress and the law which permits direct-to-consumer marketing and off-label prescription, which in turn allows BP to profitably dispense with honesty, science or FDA approval.

Counterpointing the thalidomide with the Paxil affair, then, helps us to highlight a monumental shift in culture and values that lies very deep in the neo-liberal psyche, transcending Big Pharma, the universities et al. In the thalidomide case, the culture of the 60s enabled the remarkable integrity, rigour and persistence of the FDA’s Frances Kelsey who seems to have been fully backed by the FDA directorate, though one historian of the FDA wrote that she encountered some opposition there. And where she was supported by the wider culture, which subsequently lavished awards and encomia on her, our culture both encourages and rewards the likes of Keller et al. So in 40 years the 1962 amendment, designed to ensure the efficacy and safety of drugs, was emasculated, abused and disempowered by Big Pharma PR and cynical academics. Had thalidomide arrived in 1994 and been researched by such people, the laxity of the FDA, enabled by an ethics-free drug culture, would likely have ensured its continued presence on the market for years, producing millions of deformed babies facing early death or wrecked lives. Fortunately for mothers and new-borns back then academics had integrity: and the meteoric rise of BP power, allied to the prestige and often spurious truth-value of RCTs, was still some way off. Thus a small number of early academic studies, often in the BMJ, and many “merely anecdotal” reports, succeeded in ousting the drug before it got into its stride.

But, once again, what we’re really talking about here is a seismic cultural shift, over 40 years, which is underwritten by government and the law; one which finds no place for ethics, which favours permissive drug regulation, and a neo-liberal ethos in psychiatric practice, academia and the press.

Redmond O'Hanlon

Redmond O’Hanlon is an academic who has taught university courses in Ireland, the U.S. and Oxford, where he wrote his doctorate. He is at present tidying up the final draft of a book  which attempts to bring some insights from the worlds of psychology, philosophy and the arts into critical psychiatry, with special emphasis on the importance of narrative, and on the dangerous fantasy of psychiatric diagnoses. His particular interests are depression, ADHD, trauma, the so-called personality disorders – and the greatest scam of them all, “schizophrenia.”


Whistleblower Greg Thorpe: GSK Have Used Dangerous Tactics To Drive Sales To Treat Kids

Drug firms have used dangerous tactics to drive sales to treat kids

By Christopher N. Osher and Jennifer Brown
The Denver Post

Posted:   04/14/2014 12:01:00 AM MDT | Updated:   about 8 hours ago
Whistle-blower. Greg Thorpe, a former sales representative for GlaxoSmithKline, sits at a desk in Florida with papers from the case in which he alleged the
Whistle-blower. Greg Thorpe, a former sales representative for GlaxoSmithKline,
sits at a desk in Florida with papers from the case in which he alleged
the company encouraged doctors to prescribe antidepressants to
children when the FDA had not approved the drugs for pediatric use.
Glaxo agreed to pay $3 billion to the federal government to settle the case.
(Brian Blanco, Special to The Denver Post)

Pharmaceutical companies wooed academic leaders, ghostwrote articles, suppressed damaging health data and lavished doctors with gifts to make prescribing powerful psychotropic drugs to children a blockbuster profit center, a trail of lawsuits over the past two decades shows.

As a Colorado Springs sales representative for GlaxoSmithKline, Greg Thorpe tried to put a stop to the practice. His manager wrote him up for not being a “team player” after he objected to the free spa treatments and pedicures, hunting trips, tickets to sports games and skiing junkets that his supervisors expected him to give out to doctors and others.

“The sky was the limit,” said Thorpe, whose whistle-blower lawsuit against his former employer ended with a $3 billion settlement with the federal government. “Those who spent more money got rewarded because they were positioning the company for more business. And it did pay off.”

It was just one part of the massive effort by the pharmaceutical industry to drive sales of antidepressants, antipsychotics and other psychotropic drugs to treat poor children, often for uses never approved by federal regulators.

The push succeeded in reaching a particularly vulnerable group: foster children, who experts say often struggle to cope with trauma that psychotropic drugs don’t heal.

A Denver Post investigation into antipsychotic use found that foster children were prescribed the potent mood-altering drugs at a rate 12 times higher than that of other children on Medicaid in Colorado in 2012. Dosages and rates of multidrug prescriptions also were high among foster children in this state.

Colorado officials knew about rising prescription rates and dosages of psychotropic drugs, which include antipsychotics and antidepressants, as early as 2007 but didn’t convene a panel to address the issue for more than five years.

High rates of psychotropic drug use among poor and foster children didn’t occur by mistake, government investigators say. Court documents filed in health care false-claims lawsuits show that drug companies closely tracked the prescribing habits of doctors in the Medicaid program, which pays the health care of the poor, including foster children.

In Colorado, nine of the top 10 most prescribed drugs for foster children in the Medicaid program are psychotropics, according to the most recently available data. In contrast, for non-foster children, only one psychotropic is among the top 10 most prescribed drugs in Medicaid.

Pharmaceutical companies in 2008 alone spent nearly $800 million on sales representatives making visits to health care professionals for antipsychotics and antidepressants, a December 2009 report from the nonpartisan Congressional Budget Office found.

And that’s not counting additional money paid to health care providers for speeches, consulting and research, some of which went to Colorado doctors.

John T. Hardy, an adolescent and child psychiatrist in Pueblo, received about $400,000 from 2009 through 2011 in travel, consulting and speaking fees and meals from drug companies, including antipsychotic manufacturers Eli Lilly and Pfizer, according to a ProPublica database.

A variety of psychotropic drugs — some simultaneously — are used by many children in the foster-care system. Olanzapine, sold under brand names

A variety of psychotropic drugs — some simultaneously — are used by many children in the foster-care system. Olanzapine, sold under brand names including Zyprexa, is used to treat schizophrenia and acute mixed or manic episodes, while Seroquel, or quetiapine, is used to treat nervous, emotional and mental conditions such as schizophrenia and symptoms of bipolar disorder, or manic-depressive illness. All of these drugs are atypical antipsychotics. (Helen H. Richardson, The Denver Post)

A Colorado panel studying the high use of psychotropics among foster children in Colorado reviewed Medicaid drug prescriptions and found that in 2012, Hardy was one of the highest volume prescribers in the state of mental health drugs.

“I do what’s best for my patients,” said Hardy, adding that pharmaceutical money doesn’t influence his prescribing decisions. The number of psychotropic prescriptions Hardy wrote could not be obtained by The Post.

Lucrative drugs

Far from the niche market they originally served, antipsychotics these days are some of the most lucrative drugs, with sales topping $18 billion in 2011, more than sales of vaccines and triple the amount spent on antipsychotics in 2002, national drug-sales data show.

More than 1 million children in America take antipsychotics annually, and tens of thousands of those are younger than 5, a 2009 Food and Drug Administration advisory committee study found.

One in 25 children in the nation between the ages of 12 and 17 took antidepressants in 2011, according to a study by the Centers for Disease Control and Prevention that also found that use of the drugs in Americans of all ages increased by 400 percent in the past two decades.

Pharmaceutical firms say the explosive growth has filled an important need and deny that the growth was driven by inappropriate marketing. Officials with those companies say many more people whose symptoms haven’t yet been addressed and aren’t taking the drugs could benefit from taking antidepressants and anti-psychotics.

But many child health experts warn that the increase comes at a tremendous cost to public health programs and at great risk to children. Antipsychotics have been linked to weight gain and diabetes in children and growth of breasts in boys. The FDA has warned that antidepressants increase suicidal behavior and thinking in children and adolescents.

“We really don’t know enough about the safety and effectiveness of these drugs,” said Dr. Tobias Gerhard, an assistant professor at Rutgers University who has studied the growth in prescribing antipsychotics to children and adolescents.

While antipsychotics’ effectiveness and safety remain hotly debated, the prescription of them has become standard practice for treating children for “off-label” uses that have never been approved by federal regulators.

At least three-quarters of the children prescribed antipsychotics through Medicaid took them for issues beyond FDA-approved uses for the drugs, a Rutgers University study found. The drugs often are prescribed for attention-deficit hyperactivity disorder, conduct disorder, anxiety or depression, none of which is a condition the FDA has approved for treatment by antipsychotics in children, the study found.

“It’s an issue that’s getting a lot of attention, but it’s very difficult for payers to impact the prescribing behaviors of clinicians in America,” said Dr. Stephen Crystal, who led that research team. “Major manufacturers of these drugs have paid fines in the hundreds of millions of dollars for alleged improper marketing, in some cases for use in kids.”

Doctors are free to prescribe drugs for any symptom, even if that results in a drug use that has never been approved by the FDA. But it’s against the law for pharmaceutical firms to encourage doctors to prescribe off-label.

$13 billion paid

Since 2008, pharmaceutical companies have agreed to pay more than $13 billion to resolve U.S. Department of Justice allegations of fraudulent marketing practices. Among the cases:

• Eli Lilly distributed videotapes to doctors titled “The Myth of Diabetes” when marketing its antipsychotic Zyprexa, despite being aware of studies showing those taking the drug had a higher rate of diabetes, government investigators say. The government accused the company of pressing doctors to prescribe Zyprexa to children and collected a $1.4 billion fine.

• Pfizer, which paid a $2.3 billion fine to settle a whistle-blower lawsuit, hired 250 child psychiatrists to help market its antipsychotic Geodon despite there being no approved pediatric use for the drug from the FDA. As part of the settlement, Pfizer denied any wrongdoing.

• AstraZeneca paid a fine of $520 million to resolve allegations that it promoted the antipsychotic Seroquel to treat aggression, sleeplessness, anxiety and depression when the FDA had approved the drug only to treat schizophrenia and, later, bipolar mania. Government investigators said the company targeted child physicians.

• Johnson & Johnson targeted what it called key opinion leaders to help promote the use of anti-psychotic Risperdal in children, the government alleged in another lawsuit that resulted in a $2.2 billion fine to resolve criminal and civil allegations.

The GlaxoSmithKline whistle-blower case in which Thorpe was a plaintiff included allegations the company encouraged health care providers to prescribe antidepressants to children when the FDA had not approved the drugs for pediatric use. Glaxo agreed to pay $3 billion to the federal government to settle the case, the largest health care false-claims act settlement ever.

Government investigators found that Glaxo aggressively marketed Paxil off-label as curing everything from depression to shyness in children. Increasing pediatric prescriptions of the drug was a key business strategy for the company, one that helped propel Paxil to $2.7 billion in sales in the United States in 2003, documents show.

Between 1994 and 2001, the company conducted three trials using Paxil to treat depression in those under 18. None of the trials showed the drug helped depressed children, the government asserted. But the trials showed that Paxil had harmful effects and increased the likelihood of suicidal thinking and behavior in children.

Despite those damaging findings, the company hired a firm to help it publish a favorable article about Paxil in the Journal of the American Academy of Child and Adolescent Psychiatry.

It wasn’t until 2006, two years after the FDA ordered all manufacturers of antidepressants to provide cautionary warnings on their labels, that Glaxo changed Paxil’s label to note the suicidal risk and sent letters to doctors alerting them of the risk.

Glaxo officials say the company has made broad changes to its drug-marketing policies. It no longer provides bonuses to sales representatives for increasing prescription volume. Glaxo also has begun publishing all drug-trial results and says it will stop offering to pay doctors to give speeches touting drugs.

Industry trade groups also have adopted new policies restricting the gifts that drug sales representatives can offer physicians.

But Thorpe said the changes come too late. The public still is left struggling with high prescription rates to treat the very young, he said.

“An off-label script is a script that keeps giving whether you stop promoting the drug or not,” he said. “A doctor will keep prescribing the drug if he’s become comfortable with it. The patient likes the drug, so they will want it. It becomes a profit for life.”

Thorpe said he became disgusted with Glaxo’s all-expense-paid trips to Jamaica and Hawaii for physicians and their guests to train them how to give speeches touting the drugs.

Some speakers were paid more than $500,000 annually to talk up the benefits of treating children with antidepressants when the FDA had never approved the drugs for such uses, documents show. The company budgeted as much as $6.8 million annually to entertain doctors in luxury sky-box suites at sporting venues, according to the documents.

Thorpe left the company where he had worked 24 years and later filed his lawsuit. It took nine years for government prosecutors to join the suit.

In 2012, Glaxo agreed to settle. Thorpe’s cut for helping the government recuperate money drained from the Medicare, Medicaid and veteran programs was $20 million.

Off-label uses pushed

Glaxo was not the only company to use such tactics. Other firms pushed for off-label uses of newer antipsychotics, known as atypicals, contending they worked better than older versions.

During the 1990s, Johnson & Johnson received FDA approval for its new antipsychotic drug, Risperdal, to treat schizophrenia in adults. But the agency repeatedly rejected J&J’s efforts to obtain approval for children.

The company had not proposed any child or adolescent psychiatric disorders that Risperdal would treat, the FDA noted in one denial letter. In one meeting, FDA officials worried that using the drug to treat conduct disorder in children would amount to creating a “chemical straitjacket.” It was not until 2006 that FDA officials approved the drug for the limited use of treating autism in children.

Still, the company trained its sales force to market the drug to primary-care doctors and child psychiatrists well before that 2006 approval. More than 1,500 child psychiatrists, targeted due to their antipsychotic prescribing history, each received at least 12 calls from J&J sales representatives in 2000 , documents show.

In 2003, when Risperdal still had no FDA-approved use for children, the company developed a “Back to School Bash.” The marketing plan aimed to increase prescriptions of Risperdal to children and adolescents with ice-cream parties and free snacks and lunches.

One district manager praised a sales representative for promoting a new, faster-dissolving version of Risperdal by providing starter kits to child psychiatrists. The kits included free Risperdal samples, coupons for the drugs, lollipops and small toys, a performance review shows.

Other initiatives that J&J launched for Risperdal created problems for the company.

A research partnership with a prominent child psychiatrist backfired when it was revealed that the psychiatrist and two others had accepted $4.2 million from pharmaceutical companies from 2000 to 2007.

J&J hired a marketing firm to ghostwrite articles attributed to academicians who had done little to no work, according to a report from Dr. David Rothman, a Columbia University professor who studies medical industry ties. Rothman was an expert witness for the Texas Attorney General’s Office in a lawsuit against J&J.

Along the way, the company kept from the public key health data showing troubling risks of Risperdal.

In the pediatric market, the company downplayed the risk that the drug would cause the growth of prolactin in boys, which can cause them to develop lactating breasts, said David Kessler, a former FDA chief who was an expert witness in personal-injury lawsuits filed against Janssen Pharmaceuticals Inc., a J&J subsidiary.

Kessler found the company was responsible for medical-journal articles that gave misleading information about the results of studies into the prolactin issue.

In fact, the company’s studies showed breasts developing in about 10 out of 100 children taking the drug, Kessler reported.

“Janssen’s promotion of Risperdal, a powerful drug, for nonapproved uses in the most vulnerable children is deeply troubling,” Kessler stated in his report.

Janssen officials said those activities are in the past.

“Janssen is committed to ethical business practices and has policies in place to ensure its products are only promoted for their FDA-approved indications,” said spokesman Robyn Reed Frenze. “In fact, the company’s policies meet and often exceed the legal requirements of all jurisdictions it operates within and all local industry codes of which it is a member.”

While the court settlements seem big, they don’t compare to the profits the sales of the drugs generate, said Stephen Sheller, a Philadelphia lawyer who worked with the justice department on a whistle-blower lawsuit involving Risperdal.

J&J generated $4.55 billion in annual sales of Risperdal, 18 percent of its pharmaceutical sales, according to financial reports the company filed with federal regulators in 2008.

Meanwhile, lawsuits against pharmaceutical firms alleging violations of the federal false-claims act continue to be filed at a rapid pace. The justice department says 500 health care fraud act lawsuits were filed last year, the most ever in a year.

“Nothing is going to change significantly until a few top people go to jail,” Sheller said. “There is too much money to gain by marketing the drugs illegally.”

Christopher N. Osher: 303-954-1747, or

About the drugs

Psychotropics: A broad class of medications made of chemicals that alter brain function, including mood and behavior; these include antidepressants, anti-anxiety drugs and attention-deficit-disorder drugs.
Antipsychotics: The most powerful drugs in the broader class of psychotropics; have been linked to diabetes and weight gain in children, and growth of breasts in boys.
Atypicals: The latest generation of antipsychotic medications, with brand names such as Abilify, Zyprexa and Risperdal.

About the seriesThis investigation by The Denver Post into psychotropic drug use by foster children stems from The Post’s “Failed to Death” series on Colorado’s child-welfare system that ran in 2012.
The overprescription of powerful psychotropic medication to foster children is a national epidemic — yet in Colorado, efforts to curb the problem lag some states.
The Post obtained unpublished state data and reports, interviewed foster families and children, reviewed other states’ efforts and examined promising new therapies.

Sunday: Foster kids are prescribed powerful drugs that alter brain function at rates far higher than other children. A growing number of experts say this is not only unnecessary, but harmful.

Monday: Over decades, the pharmaceutical industry pushed aggressively to market psychotropics to children and tap into the lucrative Medicaid system.

Tuesday: New therapies to repair developmental delays in children’s brains caused by abuse and neglect are taking hold. Proponents advocate for more therapy and fewer medications.

Wednesday: Other states have been more aggressive and more effective than Colorado in establishing policies to reduce prescriptions of psychotropics to foster children.

Read more: Drug firms have used dangerous tactics to drive sales to treat kids – The Denver Post
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