Whether their faculty positions are at Harvard or Stanford, one cannot discern a modicum of science to back up their treatment recommendations.
1. David Armstrong of the Wall Street Journal documents violations of medicine’s foremost ethical principle, “first, do no harm,” by influential academic psychiatrists who promote psychotropic drugs for pregnant women that will cause harm to their developing infants. Specifically, thirteen leading industry-financed psychiatrists from Harvard, UCLA and Emory, published a report in JAMA (2006) whose aggressive promotion in the local and national media was designed to frighten pregnant women and to dissuade them from stopping antidepressants during pregnancy. [1]
The authors emphasized a (previously unreported) risk of relapse, disregarding a body of evidence (documented since 1993) demonstrating that exposure to serotonin (SSRI antidepressants) in utero has caused birth defects, cardiac malformation, respiratory distress, and severe withdrawal syndrome in infants. The authors even disregarded manufacturers’ disclosure on SSRI-SSNRI drug labels which acknowledge that the drugs pose risks of harm to neonates who “have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding." (June 2004) http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#effexor
https://ahrp.org/infomail/04/06/29.php
Indeed, documented evidence of drug-induced harm in infants is mounting—most likely reflecting the widespread misuse of these drugs by pregnant women. A study of 1,213 women by Dr. Christina Chambers, published in the NEJM (2006) warned about an alarming six-fold increase in a dangerous respiratory condition–persistent pulmonary hypertension (PPHN)–among babies born to mothers who used SSRI’s late in their pregnancy. PPHN is a condition marked by severe respiratory failure, normally occurring in about one or two infants per 1,000 births. However, for babies exposed to antidepressants late in pregnancy, the rate rose to six to 12 births per 1,000. And of babies born with the condition 10% to 20% do not survive. Demonstrating their disdain for scientific evidence, Industry-paid psychiatrists at Harvard disparage Dr. Chambers’ study, arguing its findings didn’t “jibe” with their experience.
Psychiatrists who recommend antidepressants for pregnant women may be more intent on reversing declining SSRI sales than protecting infants. SSRI sales have plummeted since 2004. The percentage change between 2004 and 2005: Zoloft ($3.1 billion) down 2%; Paroxetine (generic, $0.5 billion) down 27%; Paxil (GSK, $0.3 billion) down 61%; Prozac ($0.2 billion) down 7%. Lexapro alone showed increased sales: ($2.1 billion) up 19%.
The WSJ reveals that the lead author of the JAMA report—Dr. Lee S. Cohen, a Harvard Medical School professor and director of the perinatal and reproductive psychiatry research program at Massachusetts General Hospital – “is a longtime consultant to three antidepressant makers, a paid speaker for seven of them and has his research work funded by four drug makers. None of his financial ties were reported in the study. In total, the authors failed to disclose more than 60 different financial relationships with drug companies.”
JAMA’s failure to enforce its conflict of interest disclosure policy raises serious questions about the journal’s role as a promoter of industry’s marketing agenda rather than a gatekeeper protecting the integrity of scientific and ethical standards in research.
Dr. Cohen and his co-authors would have us believe that they are not of the same human species as the rest of us when claiming “their financial links have no bearing on their research work or what they say about antidepressant use during pregnancy in interviews or lectures.” However, “he declined to specify what he does in his consulting role for the companies or how much he is paid, other than to say "we are not talking about megabucks." Dr. Cohen said "it didn’t seem relevant" for him and several of his co-authors to disclose their industry relationships in the JAMA paper in part because the study was funded by the government, not drug makers.
The WSJ reveals that Harvard Medical School Symposia for doctors, billed as “CME–continuing medical education–you can trust,” are rigged as they are almost exclusively comprised of psychiatrists with financial ties to drug makers who promote the expansive use of psychotropic drugs. Indeed, the Mass General psychiatry academy “itself is funded by six drug makers, including two antidepressant makers.”
“The work of these academic researchers highlights the role of "opinion" or "thought" leaders coveted by drug companies because of their ability to influence not only the practice of doctors, but popular opinion as well. In the case of antidepressant use during pregnancies, the industry-paid opinion leaders have become dominant authorities in the field. They help establish clinical guidelines, sit on editorial boards of medical journals, advise government agencies evaluating antidepressants and teach courses on the subject to other doctors. In some cases, the financial ties between industry and these leading researchers are not disclosed.” See: http://online.wsj.com/article/SB115257995935002947.html
2. The second report in a series by Paul Jacobs of the Mercury News (California Bay area) documenting conflicts of interest at Stanford University focuses on the substantial financial interests of its chairman of psychiatry, Dr. Alan Schatzberg who “announced with considerable fanfare” that he may have found a better way to treat depression in “a repackaged version of RU-486, the controversial abortion pill,” which he claimed, “may be the equivalent of shock treatments in a pill” without the side effects.”
Mercury News notes, “Schatzberg has more than a purely scientific interest in this particular pill. He has a financial conflict of interest.” Dr. Schatzberg “administers a $600,000-a-year federal grant, part of which pays for ongoing research at the medical school on mifepristone, the key ingredient in RU-486, in depression. He is also co-founder of Corcept Therapeutics in Menlo Park, a publicly traded company that hopes to turn mifepristone into an approved treatment for depression and other psychiatric ills. He sits on the company’s board of directors, chairs its scientific advisory board and is one of its largest shareholders. And because the company has an exclusive license from Stanford for Schatzberg’s discovery, the university also stands to profit from Corcept’s work.
“The stakes for Schatzberg, his company, the university and severely depressed patients are huge. Corcept estimates that 3 million patients could benefit from the drug. Schatzberg, whose family has paper profits of nearly $12 million from Corcept stock, could reap millions more if the company’s treatment is approved.” Dr. Schatzberg’s extensive financial ties to pharmaceutical companies are listed at: http://www.mercurynews.com/mld/mercurynews/living/education/15004544.htm?
“Such conflicts are surprisingly common in the high-stakes world of academic medical research. But what makes Schatzberg’s case unusual is that two other top research psychiatrists have publicly attacked his work and accused him of shoddy science. Schatzberg’s conflict is a lesson in how hard it can be for a leading scientist at a major medical school to disentangle his outside financial interests from his academic role.”
An unusual development (in psychiatry) is that Dr. Schatzberg’s published and public claims were challenged by two prominent psychiatrists. Mercury News outlines the details of a poster critique by Drs. Bernard J. Carroll and Robert T. Rubin who “systematically picked apart the conclusions in three published studies of RU-486 in depression, two by Schatzberg and his colleagues, one by an independent group….The poster, presented at the annual meeting of the ACNP juxtaposed positive public statements about the drug by Schatzberg and other researchers and juxtaposed those statements against the individual’s financial interest in Corcept.
There, for example, was Schatzberg saying RU-486 may be “the equivalent of shock treatments in a pill” and a statement pointing out that he owned 3 million shares of Corcept stock. The point was hard to miss: Researchers with a financial interest were expressing “considerable enthusiasm” for a treatment of questionable effectiveness.
See: http://www.mercurynews.com/multimedia/mercurynews/archive/posteranddebate.pdf
Reference:
1. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507.
Contact: Vera Hassner Sharav
veracare@ahrp.org
http://online.wsj.com/article/SB115257995935002947.html
THE WALL STREET JOURNAL
Drug Interactions: Financial Ties to Industry Cloud Major Depression Study
At Issue: Whether It’s Safe For Pregnant Women To Stay on Medication
JAMA Asks Authors to Explain
By DAVID ARMSTRONG
July 11, 2006; Page A1
For pregnant women considering whether to continue taking antidepressant drugs, a study in a February issue of the Journal of the American Medical Association, or JAMA, contained a sobering warning: Stopping the medication greatly increases the risk of relapsing into depression.
The study authors — most of them leading psychiatrists at Massachusetts General Hospital, the University of California Los Angeles and Emory University — said their results challenged a common assumption that hormonal changes during pregnancy protected expectant mothers against depression. In their article, they predicted the findings would prompt some women to stay on their depression medication through pregnancy. That was good news for the makers of big-selling antidepressants, who have recently faced growing questions about the safety of their medications when used during pregnancy.
But the study, and resulting television and newspaper reports of the research, failed to note that most of the 13 authors are paid as consultants or lecturers by the makers of antidepressants. The lead author –Lee S. Cohen, a Harvard Medical School professor and director of the perinatal and reproductive psychiatry research program at Massachusetts General Hospital — is a longtime consultant to three antidepressant makers, a paid speaker for seven of them and has his research work funded by four drug makers. None of his financial ties were reported in the study. In total, the authors failed to disclose more than 60 different financial relationships with drug companies.
Dr. Cohen and some of his coauthors subsequently hit the lecture circuit, telling physicians about their findings while also spotlighting flaws in other recent studies that have found increased risks to babies born to mothers who use antidepressants. The work of these academic researchers highlights the role of "opinion" or "thought" leaders coveted by drug companies because of their ability to influence not only the practice of doctors, but popular opinion as well. In the case of antidepressant use during pregnancies, the industry-paid opinion leaders have become dominant authorities in the field. They help establish clinical guidelines, sit on editorial boards of medical journals, advise government agencies evaluating antidepressants and teach courses on the subject to other doctors. In some cases, the financial ties between industry and these leading researchers are not disclosed.
The researchers, including Dr. Cohen, maintain that their financial links have no bearing on their research work or what they say about antidepressant use during pregnancy in interviews or lectures. The pharmaceutical companies say the academic researchers they work with provide important expertise that benefits patients. "It is important to remember that this is a partnership with the mutual goal of advancing science and enhancing patient care," says a Pfizer spokeswoman.
But such ties are prompting a growing debate in the medical community. Some physicians say they worry that it’s hard to get unbiased information about treatment options for depressed pregnant women and that safety concerns about the use of antidepressants during pregnancy are being wrongly discounted. "Whether or not to keep taking an antidepressant during pregnancy is a critical question for pregnant women suffering from depression," says Adam Urato, a Bradenton, Fla., obstetrician and perinatologist who publicly questioned Dr. Cohen and colleagues about their industry relationships during a recent online training session. "What these pregnant women and the providers who care for them need is expert advice that is free from pharmaceutical industry influence or the suggestion of bias that results when these experts are being paid by so many antidepressant manufacturers."
JAMA says its policies require that authors of studies disclose financial ties to the medical industry. JAMA’s editor-in-chief, Catherine D. DeAngelis, says the journal wasn’t aware of the relationships Dr. Cohen and some co-authors of the February article had to drug companies. "As soon as JAMA found out that they didn’t disclose, we contacted the corresponding author, Dr. Cohen, and asked for his explanation," she says. "We have one and it will be published very soon in an upcoming issue of JAMA."
Dr. Cohen said his industry relationships have no influence on his research work or public comments on the issue. He added that the drug companies "tend to pick people who are expert in this area." He declined to specify what he does in his consulting role for the companies or how much he is paid, other than to say "we are not talking about megabucks." Dr. Cohen said "it didn’t seem relevant" for him and several of his co-authors to disclose their industry relationships in the JAMA paper in part because the study was funded by the government, not drug makers.
Big Ramifications
Whether or not pregnant women continue or stop the use of antidepressants has big ramifications for makers of those drugs. Women are twice as likely to suffer from depression as men and have a 25% risk of developing depression during their lifetime, according to U.S. government estimates, with that risk peaking during childbearing years. The American Medical Association estimates that over 1% of pregnant women in the U.S., or more than 40,000, are taking antidepressants. Sales of antidepressant drugs in the U.S. last year exceeded $12.5 billion, according to IMS Health, which tracks prescription drug sales.
Recently, new concerns have been raised about the safety of antidepressants during pregnancy, mostly among the large class of drugs known as selective serotonin re-uptake inhibitors, or SSRI’s. Eli Lilly & Co.’s Prozac, Pfizer Inc.’s Zoloft and Glaxo SmithKline PLC’s Paxil are all SSRI’s. Some studies have found an increased risk of a potentially fatal breathing disorder and an increased risk of seizures and fetal death among infants born to mothers using a broad spectrum of SSRI’s, including these drugs. And two studies have found an increased risk in cardiac malformations in babies born to Paxil users. Drug makers say patients need to decide with their physician if taking an antidepressant during pregnancy is the right thing to do. "It is obviously a weighing of benefits and risks between the patient and their physician," says GlaxoSmithKline spokeswoman Mary Anne Rhyne. "We try to be as transparent as possible in providing information to factor into that analysis." Most antidepressants carry warning labels that explain the potential risks to the unborn baby.
For physicians, it is becoming increasingly complicated to balance the risks posed by antidepressant use by expectant mothers against the dangers associated with depression during pregnancy. Several studies have linked depression to premature birth and developmental delays. Depression during pregnancy is also associated with an increased risk of postpartum depression, which some researchers believe affects parenting and can result in developmental delays and behavioral problems for children.
The Cohen study was published around the same time that another study appeared in the New England Journal of Medicine warning of an alarming increase in a dangerous breathing problem among babies born to mothers using antidepressants. The study of 1,213 women, led by Christina Chambers, a pediatric researcher at the University of California San Diego, found a sixfold increase in the rate of persistent pulmonary hypertension of the newborn, or PPHN, among babies born to mothers who used SSRI’s late in their pregnancy. About 10% to 20% of babies born with the condition do not survive. The condition, which is marked by severe respiratory failure, normally occurs in about one or two infants per 1,000 births.
For babies exposed to antidepressants late in pregnancy, the rate of occurrence rose to six to 12 births per 1,000, according to the study. Dr. Chambers and another author receive research funding from several generic drug makers to study the safety of drugs taken during pregnancy to treat rheumatoid arthritis and other auto-immune diseases. The study itself was funded by government grants. In an accompanying editorial, James Mills, a senior biomedical research scientist at the National Institute of Child Health and Human Development, wrote that the association between SSRI use and the breathing problem was "very unlikely to be due to chance" and that women considering whether to use antidepressants during pregnancy should take the new findings into consideration.
After the study, Dr. Chambers says she heard from women across the country who took antidepressants and had babies born with the condition. Alexis McLaughlin of Dayton, Ohio, says she took 20 milligrams of Paxil daily during her pregnancy with her fourth child. She didn’t take an antidepressant when pregnant with her other children. Mrs. McLaughlin says her depression began after the birth of her third child. "I couldn’t stop crying," she says. "I couldn’t sleep. I looked like I was falling apart." The Paxil was effective in treating her depression, she says. She says her daughter started to experience difficulty breathing soon after coming home from the hospital. Within days, the baby was back in the hospital in the critical care unit, where she needed a respirator to breathe. After several days, the baby was diagnosed with PPHN and transferred to the children’s hospital in Cincinnati. After treatment there, the baby began to get better and eventually recovered.
The results of Dr. Chambers’s study are being questioned by industry-paid experts in the field. In a recent online symposium for doctors, Adele C. Viguera, the associate director of the Massachusetts General perinatal psychiatry program and professor at Harvard Medical School, said of the Chambers study: "We were very surprised by those findings because it really didn’t jibe with our clinical experience." She went on to say that Mass General "informally surveyed" colleagues across the country and that none of them had ever seen the problem identified by Dr. Chambers. "So I think it really underscores this point that we can’t let one study dictate our clinical care."
Dr. Viguera is a member of the GlaxoSmithKline speaker’s bureau. Dr. Viguera says she is paid to talk about Lamictal, another Glaxo drug that is used to treat bipolar disorder. She says she does about a half dozen of those talks a year and is paid $2,000 for each. Her comments came during a May 17 lecture sponsored by the Massachusetts General Hospital Psychiatry Academy. The event carried the stamp of the Harvard Medical School and bore the slogan "CME you can trust." The initials stand for continuing medical education — a certain amount of which is required of doctors annually by state medical-licensing boards. Doctors received CME credit for the May 17 event.
The panel of experts for the session on "Psychotropic Drug Use During Pregnancy" was comprised entirely of psychiatrists with financial ties to drug makers. The Mass General psychiatry academy itself is funded by six drug makers, including two antidepressant makers. These relationships were disclosed. During the hour-long Web broadcast of the panel session, Dr. Chambers appeared in a 90-second videotaped clip to explain her findings and respond to some of the criticisms from the panel.
Warning Labels
The panelists were also critical of a recent action by the Food and Drug Administration to add new warnings about potential birth defects to the Paxil label. In December, the FDA issued a health advisory saying it determined exposure to Paxil in the first trimester of pregnancy may increase the risk of congenital malformations. The advisory said an as-yet-unpublished Swedish study of 6,896 women found a doubling of cardiac defects among infants born to mothers who use Paxil, compared with those in the general population. Most of the cardiac defects involved the failure of the wall between the left and right sides of the heart to completely develop.
Panelist Zachary Stowe, who directs the women’s mental health center at Emory, described the recent FDA decision to change the warning label for Paxil as "driven by a single set of data that is unpublished, non-peer reviewed, and somehow this trumps the very nicely done prospective investigations that have really failed to find this risk." Dr. Stowe has served as an adviser and speaker for several antidepressant makers. To further make that point, a videotaped interview with Gideon Koren, the director of the Motherisk Program at the University of Toronto, was played.Dr. Koren said the data identifying a risk of cardiac malformation were "very low quality" and that regulatory agencies were "just throwing us statements, mostly for medical-legal reasons." Dr. Koren is currently conducting a study funded by drug maker Wyeth looking at the development of children exposed to the company’s Effexor, a non-SSRI antidepressant. That relationship was not disclosed.
Beginning this fall, the Mass General psychiatry academy plans to conduct CME symposiums in a dozen cities across the country. Dr. Cohen is overseeing a segment on treating psychiatric disorders during pregnancy, according to material promoting the events. Robert Birnbaum, the medical director for postgraduate medical education in the psychiatry department at Massachusetts General, said the panelists were chosen because they are nationally recognized leaders in their field. He said the academy curriculum is supported by a consortium of pharmaceutical companies, but that the drug makers have no input into the selection of faculty or program content.
Experts with industry ties were also heavily represented at a U.S. government-sponsored conference in Florida last month. The conference, sponsored by the National Institute of Mental Health, a government agency, drew hundreds of researchers from academia, industry and government.
A panel titled "Use of SSRIs and Mood Stabilizers During Pregnancy: Weighing the Risks" included Drs. Cohen and Viguera, as well as Alan J. Gelenberg, the head of the psychiatry department at the University of Arizona and the editor of the Journal of Clinical Psychiatry. The lone panelist without industry ties was Kathleen Uhl, the director of the FDA’s Office of Women’s Health. Her talk was largely a general discussion about how the FDA decides to assign various warning labels to drugs.
While the speakers made no mention of their industry affiliations during their presentations, conference attendees were provided a booklet when they registered that listed speakers and their financial relationships. Dr. Gelenberg said at the conference "probably there has been an overreaction" to recent concerns about heart defects linked to Paxil use during pregnancy. Dr. Gelenberg reports numerous consulting and speaking arrangements with several antidepressant makers. In an interview, Dr. Gelenberg said less than 5% of his income comes from pharmaceutical company consulting work and that he no longer owns stock of antidepressant makers. He said he knows of academic colleagues earning six-figure incomes from those companies. "The problem is if you want an expert on antidepressants in pregnancy, most of us have taken some industry money," he said. The solution, he adds, is more independent or government funding of research work.
Nada Stotland, a professor of psychiatry and obstetrics at Rush Medical College in Chicago, says there is a lack of good studies looking at the use of antidepressants in pregnancy. She says one problem is that pharmaceutical companies have the resources to do the studies that are needed, but "only do what they are required to do" by the FDA. She also says few studies look at non-drug alternatives to treating depression in pregnancy, such as psychotherapy.
Citing the conflicting and often confusing research on antidepressant use during pregnancy, the American Medical Association House of Delegates last month passed a measure directing the association to come up with guidelines concerning the treatment of depression during pregnancy.
The JAMA study by Dr. Cohen and others was the first major paper to establish a risk of relapse for pregnant women who stop antidepressant treatment. For many years, doctors were taught that pregnancy is a time of emotional well-being that protects women from getting depressed. The study was widely covered by print and television. Wide Publicity Headlines warned of the danger of stopping antidepressants during pregnancy, and many local television news stations broadcast, unedited, a "video news release" put out by JAMA reporting on the study. That release featured Dr. Cohen and one of his patients, Lisa Kirshenbaum of Cranston, R.I., who was a part of the study. Ms. Kirschebaum experienced a miscarriage when she went off her antidepressants, according to the video. When she became pregnant again, she took her medication and delivered a healthy baby, according to the release. The actual study, however, did not examine whether mothers delivered healthy or sick babies. It tracked only whether they suffered from depression.
The study reported financial relationships with antidepressant makers for two of the 13 authors of the study, Emory’s Drs. Stowe and Jeffrey Newport. But at least seven others have relationships that were not disclosed. Among the most significant of the missing disclosures are those of the second listed author — Lori Altshuler, director of the Mood Disorders Research Program at UCLA. She is a speaker or consultant to at least five antidepressant makers. An assistant says she is on sabbatical and unavailable for comment. Two of her colleagues — Vivien Burt and Victoria Hendrick — were also authors who didn’t report financial relationships they have with antidepressant makers. Dr. Burt, in an interview, said "we all regret not having" disclosed those relationships and are "all genuinely interested in doing the right thing at all times." Attempts to contact Dr. Hendrick were unsuccessful. Dr. Cohen says JAMA has imposed an embargo on his letter until the journal publishes it, so he can’t discuss the contents.
Dr. Viguera of Mass General was another author, and did not disclose her speaking relationship with GlaxoSmithKline. She said the study was designed in such a way that "I don’t see how any kind of relationship we have with a pharmaceutical company plays a role in that. …I don’t believe there is a conflict of interest."
Write to David Armstrong at david.armstrong@wsj.com
Copyright 2006 Dow Jones & Company, Inc. All Rights Reserved
http://www.mercurynews.com/mld/mercurynews/living/education/15004512.htm?
Mercury News
Science critics make issue of financial ties
Mon, Jul. 10, 2006
By Paul Jacobs
For more than 20 years, Stanford University psychiatrist Alan F. Schatzberg has been hunting for a better way to treat the most severely depressed patients. A few years ago, he announced with considerable fanfare that he may have found it in an unlikely place — a repackaged version of RU-486, the controversial abortion pill. It “may be the equivalent of shock treatments in a pill” without the side effects, he said in a Stanford news release. Yet Schatzberg has more than a purely scientific interest in this particular pill. He has a financial conflict of interest.
The 61-year-old chairman of Stanford’s psychiatry department administers a $600,000-a-year federal grant, part of which pays for ongoing research at the medical school on mifepristone, the key ingredient in RU-486, in depression. He is also co-founder of Corcept Therapeutics in Menlo Park, a publicly traded company that hopes to turn mifepristone into an approved treatment for depression and other psychiatric ills. He sits on the company’s board of directors, chairs its scientific advisory board and is one of its largest shareholders. And because the company has an exclusive license from Stanford for Schatzberg’s discovery, the university also stands to profit from Corcept’s work.
Such conflicts are surprisingly common in the high-stakes world of academic medical research. But what makes Schatzberg’s case unusual is that two other top research psychiatrists have publicly attacked his work and accused him of shoddy science. Schatzberg’s conflict is a lesson in how hard it can be for a leading scientist at a major medical school to disentangle his outside financial interests from his academic role. The Stanford professor says he has done everything required under the rules: He’s disclosed his corporate ties to the university and the government. He has identified them in published papers and lectures. And he’s kept a distance from RU-486 depression research on campus even while administering federal grants that pick up the costs. “The reality is when people invent something at a university and they may in fact get a royalty, they’ve created some conflict,” Schatzberg said. “But conflicts only materialize with success, when there might be a benefit.”
But two independent experts on medical statistics, asked by the Mercury News to review key papers co-written by Schatzberg about the effects of RU-486 on depression, agree with his critics: The studies published to date, they say, are not properly analyzed.
Schatzberg defends his studies as solid preliminary research and says the criticisms fail to grasp the importance of publishing promising early findings in drug development. “We’re trying to do something to help very badly ill patients and if it’s successful the field will be advanced,” he said. “I didn’t come into this because of business. What motivates me is to help people.”
The stakes for Schatzberg, his company, the university and severely depressed patients are huge. Corcept estimates that 3 million patients could benefit from the drug. Schatzberg, whose family has paper profits of nearly $12 million from Corcept stock, could reap millions more if the company’s treatment is approved.
Unusual dispute
As its tongue-twisting name implies, the American College of Neuropsychopharmacology is dedicated to research that probes the workings of the brain. Schatzberg is a past president. Members try not to miss its annual meeting, typically held in December in a warm climate. It was at the 2004 meeting in San Juan, Puerto Rico, that Schatzberg’s critics publicly unveiled their critique of his work in the form of a poster — really a scientific paper in outline form, pinned to a board in an exhibit hall. The contents were explosive.
The poster, by Drs. Bernard J. Carroll and Robert T. Rubin, systematically picked apart the conclusions in three published studies of RU-486 in depression, two by Schatzberg and his colleagues, one by an independent group. But in a departure from the usual give and take of scientific debate, the poster quoted positive public statements about the drug by Schatzberg and other researchers and juxtaposed those statements against the individual’s financial interest in Corcept. There, for example, was Schatzberg saying RU-486 may be “the equivalent of shock treatments in a pill” and a statement pointing out that he owned 3 million shares of Corcept stock. The point was hard to miss: Researchers with a financial interest were expressing “considerable enthusiasm” for a treatment of questionable effectiveness.
The poster was seen by many of the top brain scientists in the country, people whose opinions matter deeply to Schatzberg as well as his critics. Carroll, former head of psychiatry at Duke University and now semi-retired in Carmel, recalls that people came up to him during the session, slapped him on the back and said, “It’s about time somebody said this.”
But he and Rubin soon learned that other members, Schatzberg among them, were furious. A lawyer for Corcept says the ACNP admonished Carroll and Rubin for their conduct. Both Carroll and Rubin say they were faulted for making their criticisms public, not for the content of the presentation.
Even now, Schatzberg can hardly contain his anger. “Those that are critical,” he said, “ought to be careful about impugning others.”
In his genes: Medicine and psychiatry seem to be in Alan Schatzberg’s genes. His father was a general practitioner in New York. His sister, brother-in-law and niece are all psychiatrists. “When I got out of medical school in 1968,” he said, “biological psychiatry was just starting and I found it fascinating.” The talk therapy pioneered by Sigmund Freud was making room for chemistry. Patients who might have spent the rest of their lives in psychiatric wards were being sent home with prescriptions, and a new generation of drugs would become billion-dollar-a-year blockbusters.
After completing his training and a stint in the U.S. Air Force, Schatzberg joined Harvard’s renowned McLean Hospital, famous for its treatment of celebrity poets like Robert Lowell, Anne Sexton and Sylvia Plath.
By the 1980s, Schatzberg and a junior faculty member, Dr. Anthony J. Rothschild, had worked out a theory to explain the underlying cause of what they believed to be a distinct disease, “psychotic major depression.” These were patients who not only were profoundly depressed, but who also might believe they were being tailed by the police, that their co-workers were out to get them or that the devil was taking control of their thoughts. The standard treatment is electroshock or a combination of drugs. But electroshock requires general anesthesia, causes memory loss and is expensive. And the drugs can cause weight gain, diabetes and uncontrolled movements. Schatzberg and Rothschild came to believe that high levels of the stress hormone cortisol might explain what was happening to their gravely depressed patients. They speculated that a drug to block cortisol could be an effective treatment.
Ironically, this idea was partly based on earlier work by Carroll and Rubin, now Schatzberg’s outspoken critics.
The main ingredient in RU-486 is mifepristone, a chemical known to block cortisol. But because of the controversy surrounding abortion, RU-486 was then impossible to obtain, said Rothschild. In 1991, Schatzberg became chairman of the psychiatry department at Stanford, where he continued his work on depression. When RU-486 became available for research a few years later under President Clinton, Schatzberg and Dr. Joseph K. Belanoff, a young psychiatrist on a fellowship in the department, began testing the pill in a handful of severely depressed patients. They were encouraged by the results of their pilot study, funded by a National Institutes of Health grant. So was the university. In 1997, Stanford applied for a patent covering mifepristone and related compounds when used to treat depression. Schatzberg and Belanoff would each be entitled to a 14 percent cut of any licensing fees and royalties paid to the university.
The university’s technology licensing office, which files patents and markets the rights, made the rounds of the big drug companies. But because of the political issues surrounding RU-486, “they didn’t want to touch it,” Schatzberg said. “We had a drug that could help the most severely ill people, people who are at risk of killing themselves, killing their kids, dying because of medical illness, who might be helped by a very interesting and remarkable treatment that could be an alternative . . . to shock treatments.” The only option, he said, was to start a company, something dozens of Stanford medical researchers had done before him.
Creating conflict
With the backing of Silicon Valley biotech investors, Schatzberg and Belanoff in 1998 founded Corcept Therapeutics. The start-up obtained the exclusive license for the Stanford patents that no one else seemed to want. In exchange, the university got 10,000 shares of company stock plus annual fees and milestone payments. Belanoff became the company’s full-time chief executive officer. Schatzberg took a seat on the board of directors and a part-time post as chairman of the company’s scientific advisory board, a job that now pays him $60,000 a year. He and his family were granted 3 million Corcept shares for $1,000 — today worth nearly $12 million. He remained head of his department at Stanford, and continued as the principal investigator on several NIH grants, today totaling more than $1.3 million a year.
Beginning in 2000, Corcept sponsored a trial that recruited patients at six universities, including Stanford. Schatzberg, who says he played no direct role in the study, and the university had a substantial stake in the outcome of the trial — and a classic conflict of interest.
Stanford had no conflict of interest committee at the time, so he reported his financial ties to the dean’s office. After the committee was put in place in 2001, Schatzberg went before it “to discuss in detail my research activities and my relationship with Corcept in order to ensure a clear separation of these interests.” Once the company was formed, Schatzberg decided he could no longer play a direct role in RU-486 studies in depression. But he remained principal investigator with overall responsibility for NIH grants that have paid for ongoing Stanford research on the drug Corcept hopes to market. Schatzberg says he helped design the RU-486 studies being conducted on campus but leaves it to others to recruit patients, administer treatments and analyze results. Monitoring committees at NIH and Stanford review the studies to ensure patient safety.
However, Schatzberg acknowledges that he has considerable influence over the junior faculty members doing the studies. As chairman of psychiatry, he helps set their salaries and can affect their career advancement. And he continues as a co-author of the resulting papers. Annually, he reports his Corcept holdings and his many other outside financial interests to the medical school’s conflict of interest program manager. And he generally discloses his interest in Corcept, as well as other companies, when submitting professional papers or giving talks. The med school’s dean, Dr. Philip A. Pizzo, agrees that Schatzberg has played by the rules, describing him as “a person of high integrity.”
Disclosure is a key element in the university’s approach to dealing with conflicts like Schatzberg’s. But one study, by Don A. Moore and others at Carnegie Mellon’s Tepper School of Business in Pittsburgh, suggests that disclosure can have the opposite of the intended effect.
Dr. Jerome P. Kassirer, a former New England Journal of Medicine editor, puts it this way: “Once they’ve disclosed their conflicts, people feel pretty free to say whatever they want to say.” Another safeguard, put in place by Stanford in December 2002, requires that the university divest shares in companies like Corcept that have treatments being tested on campus, said Paul Costello, chief of communications at the medical school.
It did not do so until May 2004 — a few months after Corcept went public. The university gave the proceeds — about $100,000 — to Lucile Packard Children’s Hospital, which is affiliated with Stanford. However, the university continues to have a conflict: If Corcept succeeds in developing RU-486 for depression and other disorders, Stanford will get additional royalty and milestone payments. So far, Stanford has collected about $400,000.
`Dramatic’ results
Two years after Corcept was founded, Schatzberg described the results of the small NIH-funded pilot study in Stanford Report, the university’s weekly faculty and staff newspaper. In four of the first five patients, the results were “fairly dramatic,” Schatzberg said. “They stopped hearing voices and having pessimistic kinds of delusions, like they’re dying or the world is ending,” he was quoted as saying. “What’s interesting is that the results are not effervescent. The patients feel better and it lasts.” The piece, which is still posted on Stanford’s Web site, does not mention Schatzberg’s financial ties to Corcept. By June 2001, on the strength of these early findings, Corcept had raised $29 million from private sources. Four months later, the results of the five-patient pilot study were published in a scientific journal, claiming “a rapid reversal of psychotic depression.” Just before Christmas that year, Corcept filed plans with the Securities and Exchange Commission to raise as much as $90 million in an initial public stock offering. While the company waited to issue stock, Schatzberg, Belanoff and others reported in the journal Biological Psychiatry the results of the larger Corcept-sponsored study of RU-486 in 30 patients at six academic centers, including Stanford. Nearly two-thirds of the subjects who received higher doses, the study said, showed “significant reductions in their psychosis” during the one-week trial.
Enter the gadflies
Bernard Carroll recalls first reading the Biological Psychiatry study in his home-office in Carmel, where he runs his non-profit institute, the Pacific Behavioral Research Foundation. “The `spin’ was unmistakable,” Carroll said. His reaction, he said, was “sadness and dismay at the low standards evident in the report and in the editorial commentary.” That commentary, written by the journal’s editors, described the work as a possible “paradigm shift in the treatment of depression.” Later that afternoon, he got a call from his friend Robert Rubin, then a professor of psychiatry at Drexel University and Allegheny General Hospital in Pittsburgh. The two had become self-appointed guardians of scientific rigor in psychiatric research — gadflies who periodically fire off salvos to journals to complain about papers that don’t measure up to their standards.
They sent such a letter to Biological Psychiatry. They criticized Schatzberg for claiming the drug “may be the equivalent of shock treatments in a pill.” They accused the authors of “obfuscation” and the editors of ignoring the study’s “fatal flaws.” Schatzberg and Belanoff responded, saying the letter was an “ad hominem attack,” and that Carroll and Rubin had “cut and pasted snips of quotes . . . and mis-characterized what we said.”
Weighing what to do with this unusually heated exchange, the journal’s editors sent the correspondence to four outside, anonymous reviewers, who split, two and two, on whether the letter and response should be published. In the end, the editors decided not to print the exchange, setting the stage for Carroll and Rubin to go public in Puerto Rico.
“It was the suppression of our considered critique that caused us to pay increasing attention to Corcept’s claims,” Carroll said.
Schatzberg, however, says the failure of Biological Psychiatry and other journals to publish letters from Carroll and Rubin shows that their criticisms are not credible. “These studies were not designed to allow you to really apply statistics,” he said. That is one of the critics’ biggest complaints: They argue that all the studies of RU-486 in depressed patients published to date either do not apply statistical methods or do so incorrectly.
Carroll calls them “experimercials” — a word he coined to describe scientific studies that create positive publicity for a particular prescription drug product. “If there is an effect, they haven’t produced the evidence,” said Carroll. “The closer you look, the more confused they appear to be, blinded to the data in their own studies because of commitment to their own therapy.”
“Until I’m shown otherwise, it’s a house of cards,” said Rubin, now chief of psychiatry at the Veterans Affairs of Greater Los Angeles and a professor at UCLA. Two independent experts asked by the Mercury News to review the three key RU-486 studies co-written by Schatzberg side with Carroll and Rubin. University of California-San Francisco Professor of Medicine Stanton A. Glantz, the author of “Primer of Biostatistics,” found several statistical errors in the papers he was asked to look at. “These are elementary statistical methods,” he said. “They have applied them incorrectly.” The result was to “bias their results toward reporting an effect when the data doesn’t justify that. Scientists shouldn’t make these dumb mistakes.” The other expert is Steven G. Self, a professor at the University of Washington, who heads the program in biostatistics and biomathematics at the Fred Hutchinson Cancer Research Center in Seattle.
Commenting on the 2002 paper in Biological Psychiatry, he said, “there is no evidence at all” for a meaningful difference in the response of patients given high doses of RU-486 and those given a very low dose presumed to have no effect at all. All you have to do is look at the data, he said, to see this. “No formal statistics are required.”
Schatzberg said that applying statistical analyses to these small, preliminary case studies is “absolutely silly.” And Corcept CEO Belanoff agrees.
Schatzberg contends that Carroll and Rubin have distorted what he’s said and harbor professional jealousies because their own work on cortisol did not result in new treatments. He also suggests their grievances have nothing to do with his science. Carroll said he was briefly hired by Schatzberg as a consultant on a five-year federal grant and given a courtesy Stanford appointment. He acknowledged he was paid $2,000 — not the $10,000 he thought he was entitled to. But Carroll said he is satisfied with the resolution. Rubin was passed over for a committee chairmanship of a psychiatric society when Schatzberg was president — a position he got the following year. Both men deny that any personal slight or dispute played a role in their criticisms of Schatzberg. Responded Carroll: “It’s a smear.”
Everyone, including Schatzberg, agrees it will take large, carefully conducted studies to establish whether the drug is an effective treatment.
Eight years after it was founded, Corcept Therapeutics is pouring its money into doing just that. Corcept remains a small company, with just 11 full-time employees last year. Much of the company’s work — manufacturing RU-486, testing it in patients and developing related drugs — is farmed out to other firms. The company has completed two large, 200-patient trials of RU-486 in depression.
In one of those trials, four patients died, said Corcept CEO Belanoff, but three of those were in the comparison group, which was not given RU-486. The deaths, he said, were reported to the FDA, which allowed the trials to proceed. “The real point is that these are sick people, period, medically as well as psychiatrically.” While Corcept reported positive findings in both trials, neither delivered the statistically significant results needed to win FDA marketing approval. Worse still, for a drug hailed as a replacement for shock therapy, only “a very small number of patients” exhibited no symptoms, according to company filings.
To satisfy the FDA, the company is conducting two additional trials in the United States and a third in Europe, which could decide whether Schatzberg is finally vindicated. Results are expected later this year. Schatzberg said he has made little money from his efforts. As part of the initial public offering in 2004, he offered to sell up to 750,000 shares of his stock at the IPO price of $12, but demand was weak and his shares were not sold. Last year, he made $109,000 selling some of his holdings. But money is not what his work on RU-486 is all about, he said.
“We hope that in 2006 you’re going to write a robust story about a breakthrough treatment that others have maligned,” Schatzberg said. “In the end the data will tell us if we’re correct or not, and we hope we are correct.”
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Contact Paul Jacobs at pjacobs@mercurynews.com or (530)756-0236.
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Dr. Alan F. Schatzberg, Stanford’s long-time chair of the department of psychiatry, has reported financial interests with a number of companies that make psychiatric pills and devices, including:
Abbott Laboratories Inc.: consultant or scientific advisory board
Bristol-Myers Squibb: consultant or scientific advisory board; grant support
Corcept Therapeutics: scientific advisory board chairman; board of directors; stock
Elan Pharmaceuticals: stock or options
Eli Lilly and Co.: consultant or scientific advisory board; grant support
Forest Laboratories: consultant or scientific advisory board
GlaxoSmithKline: consultant or scientific advisory board; grant support
Janssen Pharmaceutica Products: consultant or scientific advisory board
Merck: stock or options
Neuronetics: consultant or scientific advisory board
Organon Pharmaceuticals: consultant or scientific advisory board
Pathway Diagnostics: stock or options
Pfizer: consultant or scientific advisory board; stock or options
Sanofi-Aventis: consultant or scientific advisory board
Somaxon Pharmaceuticals: consultant or scientific advisory board; stock or options
Somerset Pharmaceuticals: consultant or scientific advisory board; grant support
Wyeth Pharmaceuticals: consultant or scientific advisory board; grant support
Source: American Psychiatric Association; Corcept Therapeutics