Sunday, September 28, 2008

Internal documents reveal extent of Paxil drug study chicanery

When I was a reporter for The Boston Globe in the 90s, an employee of Brown University's department of psychiatry handed me a raft of internal university documents. A number of these documents pertained to an ongoing clinical trial that compared the antidepressant Paxil to a placebo and older antidepresssant (imipramine) in the treatment of depression in adolescents. My book, Side Effects tells the story of how researchers at Brown University misrepresented data in this key clinical trial, known as study 329, so in the interest of transparency, I am posting these and other pertinent documents on my website.

The first document here is from the final GlaxoSmithKline report of study 329 (publicly available on its website), which shows that a 14-year-old boy who was in the Paxil arm of the study lost control, punching pictures, breaking glass and injuring himself in November 1994. He was hospitalized and seen as suicidal by the psychiatrists treating him. Yet this patient , known as #65 in the study, was not labeled as suicidal when the study was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry. (The following year, Paxil became the most widely prescribed antidepressant in the U.S.).

The second document here is a memo to Brown University's Institutional Review Board from Martin Keller, chief of psychiatry at Brown and principal investigator of study 329. In the memo, Keller reports that a teenager in the Paxil study was hospitalized in September 1995 due to becoming combative and suicidal. Yet in the memo, Keller says he has labeled this patient (#106) as noncompliant instead of suicidal as a result of taking Paxil. Likewise in the published 2001 study, this teenager is labeled noncomplaint and not included in the list of adolescents withdrawn from the study as the result of adverse side effects.

The third and perhaps most mysterious document is a memo from Keller to the IRBs at Brown and two of its affiliated hospitals, Butler and Bradley. In this January 30, 1995 memo, Keller reports that a teenage girl, patient #70 in study 329, ingested 82 Tylenol pills on January 19 and was hospitalized at St. Ann's Hospital. She was discontinued from the study at the end of January and coded as noncompliant according to another memo from Keller to Brown's IRB here. Yet according to the GlaxoSmithKline's final report, patient #70 in the same study was a 12-year-old boy enrolled in the trial on February, 22, 1995 and withdrawn on March 24 after suffering from chest pains. This patient had been randomized to the imipramine arm of study 329.

So the question remains: how did patient #70 go from being a teenage girl who overdosed on Tylenol to a 12-year-old boy with chest pains?

As I report in my book, Donna Howard, the former assistant administrator in Brown's department of psychiatry who gave me the internal Brown documents, said the data in study 329 was changed to satisfy the study's sponsor, SmithKline Beecham (which later merged with another company to become GlaxoSmithKline).

"Everybody knew we had to keep SmithKline happy and give them the results they wanted," Howard said. And she reiterated that comment last week when she was interviewed by Brown's own student newspaper, The Daily Herald.

In an editorial accompanying the news article, The Daily Herald editors raised the issue of why the university seemed to be judging faculty members by a different standard than it judges students who misrepresent or falsify data. Good question!

Tuesday, September 23, 2008

Student newspaper gives Brown a black eye

In June when the news broke that U.S. Senator Charles Grassley was probing the financial ties between Martin Keller, the chief of psychiatry at Brown University, and the drug industry, Brown officials tried to stonewall the entire issue. They refused to acknowledge that Grassley was seeking information from the university about whether Keller failed to fully disclose his myriad conflicts of interest with the very companies whose drugs he was studying and touting in medical journals and at conferences; see back story here.

Now, Brown's own student newspaper, the Brown Daily Herald, has leaped into the fray, with an indepth story on Keller and the problems with a key study of Paxil in adolescents, of which he was the principal investigator. The Herald cites my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial and research by Australian researchers, which both found the same thing: that Keller and his co-authors had misrepresented data in this clinical trial, known as study 329, that made Paxil look safer and more effective than it really is.

The student reporters who wrote The Herald story did their homework, reaching out to all the parties involved in this sordid tale, including Keller (who declined to talk), Donna Howard, the whistleblower whose inspiring story I chronicle in my book, and several Brown faculty members who remain baffled as to why Brown has taken no public action against Keller. They also quote university officials, who, true to form, said the university "can't discuss particular cases of possible claims of wrongdoing..."

Now that the cat's out of the bag at Brown, will they be more forthcoming? Stay tuned...

Wednesday, September 17, 2008

What the New York Times article on bipolar children didn't say...

I have to say I'm disappointed with the cover story on bipolar children in Sunday's New York Times magazine. The author, Jennifer Egan, raises the interesting question about why there has been such a sharp increase in the diagnosis of childhood bipolar disorder, but she fails to note a few salient facts, for instance, that this controversial diagnosis has been championed by psychiatrists who have earned millions of dollars in personal consulting fees from the very companies who make the anti-psychotic drugs used to treat this disorder.

Egan does throw in this line, "And of course, there are pressures and blandishments from the pharmaceutical industry, which stands to profit mightily from the expensive drugs -- often used in combination -- that are prescribed for bipolar illness, despite the fact that very few of these drugs have been approved for use in children." But a few paragraphs later, when she mentions Joseph Biederman, a psychiatrist at Massachusetts General Hospital and one of the fiercest proponents of using powerful drugs to treat young children for bipolar disorder, she neglects to mention that Biederman is being investigated by the Senate Finance Committee for failing to fully disclose that he earned at least 1.6 million dollars in personal income from the companies that make these expensive drugs.(back story).

That's a glaring omission in my view.

In her lengthy, 9,500-word article, Egan also fails to note the link between mania and the SSRI antidepressants, which I write about in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial. Research has shown that in some children and adults, taking antidepressants like Prozac, Paxil and Zoloft, actually induces manic behavior. So the question becomes: which came first, the predisposition to bipolar disorder, which is accentuated by the use of antidepressants, or the drug-induced manic behavior, which then leads doctors to label as bipolar patients who are taking the drugs for depression?

Throughout the piece, Egan seems to favor a completely biological explanation for bipolar disorder. She fails to consider that in some children, the mood swings, hostility and irritability that are characteristic of a bipolar diagnosis, may have been caused or exacerbated by family issues, parenting difficulties, sibling rivalries, divorce, etc. Near the end of her opus, she briefly mentions that some bipolar children appear to get well as they get older, but instead of following that intriguing observation into what could have been an interesting examination of the interplay between nature and nurture, she swerves off into a discussion of the search for "biological markers" for bipolar disorder, as if it's just a matter of time till we find some.

It's almost as if Egan is willfully ignoring the published research here. Doesn't she know that scientists have tried for years to find biological markers for schizophrenia and similar disorders and failed? When it comes to mental illness, the answers are simply not as clear-cut as Egan would have us believe.

Wednesday, September 10, 2008

Can America's premier psychiatric assocation heal itself?

Judging by its response to the Senate Finance Committee, the leadership of the American Psychiatric Association (APA) still doesn't seem to get it. For the past several months, the Finance Committee has been investigating conflicts of interest between academic psychiatrists and the drug industry and in July, the committee widened its probe to include the APA, which represents most of the nation's psychiatrists; see (back story). Sen. Charles Grassley (R-Iowa), the ranking Republican on the Finance committee, demanded that the APA cough up detailed information about the revenue that the organization has received from drug companies since January 2003.

Grassley shone his spotlight on the APA shortly after the publication of my book, Side Effects, which reveals in detail the longstanding and mutually beneficial relationship that the APA has had over the years with the pharmaceutical industry. Beginning in the 1990s and continuing to the present, drug companies have paid the psychiatry profession’s trade association millions of dollars to sponsor industry symposiums at the APA’s annual meeting each year. Speakers at those well-attended symposiums often talk up drugs made by the same companies sponsoring their talks.

The conflicts that exist in the psychiatric community go far beyond that, of course. In Side Effects, I chronicle the millions of dollars that one academic psychiatrist, Martin Keller, chief of psychiatry at Brown University, was getting paid in consulting and speaking fees by the very drug companies whose drugs he was studying and touting in medical journals and at APA conferences. Keller is among the psychiatrists being probed by the Senate Finance Committee (back story). Another psychiatrist under Grassley's spotlight whom I also mention in my book is Alan Schatzberg, chief of psychiatry at Stanford University and president-elect of the APA (back story).

This past Monday, Nada Stotland, current president of the APA, wrote a long memo to the association's members explaining that the requested information was delivered to Sen. Grassley's office on Sept. 2, along with a letter explaining the revenue information. In her Sept. 8 memo, Stotland said the letter could be "accessed at APA's website by logging into the Members Corner and clicking on Grassley response." In other words, only paying members can access the letter, not to the general public. The APA's communications office has yet to respond to my request for a copy of the letter. Transparency this is not.

In her memo, Stotland makes it sound as though she's not exactly on board with the recent calls for reform. She writes, "Long traditions and established practices are not only being questioned, but also criticized across the board. Both the American Medical Association and the Association of American Medical Colleges have developed or are developing new standards that differ sharply from many decades of practice." It almost sounds like Stotland's problem is with the criticism of these longstanding practices, not the practices themselves.

Stotland does go on to say that well before Grassley's request (last March), the APA had put together several work groups to examine the extent of her organization's reliance on drug company funding and to establish guidelines for individual psychiatrists who take money from drug companies. However, the guidelines work group has yet to have their first conference call, according to Paul Appelbaum, director of the division of psychiatry, medicine and the law at Columbia University College of Physicians and Surgeons, who is chairing the latter group.

Appelbaum says he expects his group to examine the whole range of possible conflicts that emerge when psychiatrists are paid speaking and consulting fees by drug companies and given free meals, junkets and drug samples by company reps.

In his interview with me yesterday, Appelbaum sounded a less equivocal note than Stotland. "Merely because something has been a long-established practice is not justification for it to continue," he said. "I think in general we ought to be worried about money that flows from interested parties to researchers because it has the potential to alter their research findings and distort people's judgement."

It's good to see that somebody in a position of responsibility at the APA understands what's at stake here.

Wednesday, September 3, 2008

Antidepressants and Suicide Rates: Another Salvo in the Debate

Remember all those dire warnings from the psychiatric community that youth suicides would rise after the FDA put black box warnings on antidepressants in late 2004? The argument was that physicians would be scared away from prescribing these drugs for depressed youth, leading to a rise in suicide rates.

Well, guess what? The opposite seems to have happened.

Not only did the number of antidepressant prescriptions actually rise in 2005, according to a report from the U.S. Agency for Healthcare Research and Quality this summer. But a new analysis published this week in the Journal of the American Medical Association found that the rate of suicides among youth aged 10 to 19 years actually fell by 5.3 percent between 2004 and 2005 -- to 4.49 per 100,000 kids.

The authors of the JAMA research letter did note that overall youth suicide rates for both 2004 and 2005 were still greater than the rates in earlier years. But they declined to attribute the bump solely to the FDA boxed warnings. Indeed, they noted that a lot of other factors could be at work here -- alcohol use, access to firearms, the influence of online social networks and even suicides among U.S. troops.

And that is precisely what I concluded in an opinion piece I wrote for The Boston Globe a year ago. In that op-ed, I also noted that suicide rates have long been trotted out as a public relations tool by drug companies intent on selling antidepressants. Yet there is no evidence that the use of drugs such as Prozac, Paxil, Zoloft and Celexa contributed to a decline in youth suicide rates from 1995 to 2003. Indeed, as a number of epidemiologists have pointed out, suicide rates among children (and adults) were going down well before the new class of antidepressants (SSRIs) hit the market.

Conversely, there is no evidence of a link between the FDA black box warnings and the uptick in youth suicide rates in 2004 (which, as it turns out, occurred before the black warnings went into effect).

In the end, of course, such statistical navel-gazing doesn't mean much. As Julie Zito, associate professor of pharmacy and psychiatry at the University of Maryland, said in my book, Side Effects, "People who are specialists in statistics know you have to look at trends over years and years."

So until we have some long-term data to work with, we should take any new salvos in the debate over antidepressants and suicide rates -- pro or con -- with a healthy dose of skepticism. Especially since several authors of the latest analysis have received resesrch funding or consulting income from companies that make antidepressants.