money & depression
Wall Street Journal - July 11, 2006
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
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.”