Drug Interactions Financial Ties to Industry Cloud Major Depression Study

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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, 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_

(http://online.wsj.com/quotes/main.html?type=djn & symbol=lly) & Co.'s Prozac,

_Pfizer_

(http://online.wsj.com/quotes/main.html?type=djn & symbol=pfe) Inc.'s Zoloft and

_Glaxo

Kline_ (http://online.wsj.com/quotes/main.html?type=djn & symbol=gsk) 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

GlaxoKline spokeswoman 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 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, 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. is

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 GlaxoKline 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.

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, 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 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 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 GlaxoKline. 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. "