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Debate
Resumes on the Safety of Depression's Wonder Drugs
by Gardiner Harris, New York Times, August 7, 2003
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Warnings by drug
regulators about the safety of Paxil, one of the world's most
prescribed antidepressants, are reopening seemingly settled
questions about a whole class of drugs that also includes Prozac
and Zoloft.
Doctors are just beginning to react to the finding — reported
first by British drug authorities in June and then endorsed the
next week by the Food and Drug Administration — that unpublished
studies about Paxil show that it carries a substantial risk of
prompting teenagers and children to consider suicide.
Because the studies also found that Paxil was no more effective
than a placebo in treating young people's depression, the
regulators recommended that doctors write no new Paxil
prescriptions for patients under 18. Experts say that the
suicide risk is highest in the first few weeks young patients
are on the drug.
The concern that Paxil and drugs like it could cause suicide had
been weighed, and rejected, by regulators a dozen years ago,
amid early concerns about the group of antidepressants known as
selective serotonin reuptake inhibitors, or S.S.R.I.'s. In the
meantime, millions of people have taken the drugs, and many
experts say that they have prevented far more suicides by
teenagers and children than any reading of the new findings
suggests they could have caused.
Almost no one suggests that Prozac, Zoloft, Paxil and their
cousins are not safe for the vast majority of adults, although
studies have shown them to be only modestly effective.
Still, the warnings have the early critics saying they feel
vindicated. Plaintiffs' lawyers who have uncovered evidence that
they say shows drug makers withheld evidence of the S.S.R.I.'s
suicide risk from regulators say the warnings give fresh urgency
to their claims.
And the findings have unsettled some of the very experts who
absolved S.S.R.I.'s of a link to suicide a dozen years ago. Of
the 10 American specialists who, as members of an ad hoc F.D.A.
panel, formally cleared the drugs of a link to suicide in 1991,
seven now say that the new information would prompt them to
reconsider that decision, if they were asked.
"In 1991, we said there wasn't sufficient evidence to support a
link between these drugs and suicide," said Dr. Jeffrey A.
Lieberman, a professor of psychiatry and pharmacology at the
University of North Carolina and a member of the panel. "Now
there is evidence, at least in children, and I wouldn't rule out
that it's in adults, too."
British health authorities have promised to "urgently" examine
the implications of their findings for adults. The F.D.A. is
considering whether to impose new restrictions on the use of the
antidepressants. The agency's warning emphasized that younger
patients "should not discontinue use of Paxil without first
consulting their physicians," adding, "it is important that
Paxil not be abruptly discontinued."
While the regulators' warnings address only Paxil, many of the
experts on the 1991 panel said all S.S.R.I.'s act similarly in
the body, so concerns about one could apply to all.
The drugs' manufacturers, which sell billions of dollars of
S.S.R.I.'s every year, have treaded carefully in responding to
the warnings. Without criticizing the regulators, they maintain
that there is no proof that their drugs have a link to suicidal
thinking in young patients — and they point out that the F.D.A.
in the past found no merit in such claims.
"We're trying right now to look at this issue with the F.D.A.
and come up with an understanding together of what the data
mean," said Dr. Philip Perera, a medical director of
GlaxoSmithKline, the British company that makes Paxil. Pfizer,
the maker of Zoloft, said that its drug was different from Paxil
and had passed all F.D.A. safety evaluations, including one as
recently as June 12. Eli Lilly & Company said that Prozac does
not cause suicides.
So far, there is little evidence that the warnings have affected
doctors' prescribing practices. Teenagers and children account
for about 5 percent of S.S.R.I. prescriptions, and companies
that track the industry have detected no falloff in sales.
"I can hardly imagine working without these drugs," said Dr.
William Schreiber, a Louisville, Ky., internist. "These are good
drugs, and I think they're safe drugs."
But the warnings are beginning to seep into doctors' awareness.
Connecticut officials, for example, last month dropped Paxil
from their list of approved medications for foster children. And
even doctors who do not believe there is a link between
S.S.R.I.'s and an increased risk of suicide are emphasizing that
patients need to be closely monitored in their first weeks on
the drugs.
"See them every day, if you need to," Dr. Perera of
GlaxoSmithKline said.
The drugs are widely prescribed by general practitioners, who do
not have the same training in depression and treatment as
psychiatrists.
With S.S.R.I.'s now the most prescribed drugs for depression, it
is easy to forget how high passions ran when the F.D.A. convened
an expert panel in 1991 to weigh claims that Prozac and other
S.S.R.I.'s may cause some patients to become suicidal. The
panel's hearing in Bethesda, Md., was mobbed; its chairman wore
a bulletproof vest.
Dozens of people told stories like the one related by Melinda
Harris. Blaming Prozac, she described how her father came into
the kitchen one morning, picked up a 12-inch butcher knife and
stabbed himself repeatedly in the stomach.
Just as emotionally, advocates for the mentally ill pleaded with
the panel to reassure patients that they could take Prozac with
confidence. Representatives of Eli Lilly cited studies finding
no connection between suicide and the drug, which had been on
the market for almost four years.
Despite the sharp conflict, the panel voted unanimously in
Prozac's favor, and the controversy died down. To this day, the
panel's findings are cited to rebut claims that the drugs can be
harmful.
But some of the early critics say the warnings demonstrate their
prescience. "I feel vindicated," said Joseph Glenmullen, author
of "Prozac Backlash," a fierce critique of antidepressants.
"These companies have vehemently denied this side effect for
over a decade, and now their own data indicate there's a
significant risk."
The British regulators said that their analysis of the nine
studies of Paxil found 3.2 times the likelihood of suicidal
thoughts or suicide attempts among teens and children given the
drug as among patients given a placebo. They also said that
Paxil has not proved effective against depression in children
and teenagers.
Some experts suspect that in the first few weeks of therapy,
drugs like Paxil can shove a small number of patients toward a
mental precipice, perhaps because they can cause a severe form
of restlessness known as akathisia. Patients who make it through
the first weeks of drug therapy uneventfully do fine on the
medication on the long term, these experts say.
Teenagers and children seem particularly vulnerable, said Dr.
Mark A. Riddle, director of the division of child and adolescent
psychiatry at the Johns Hopkins Children's Center.
"Kids tend to get quite activated, especially on adult doses of
S.S.R.I.'s," said Dr. Riddle, who in 1991 conducted one of the
first studies of the drugs in younger patients. "We had a lot of
cases of kids who became so disinhibited they did reckless
things," he said, describing those early findings.
In recent years, most debate among doctors and researchers about
the S.S.R.I.'s has focused on whether they are effective, rather
than whether they are safe.
Dr. David Shaffer, a researcher at Columbia University, noted
that teenage suicides have fallen significantly in every country
where Prozac and its cousins are in widespread use.
"This amazing, undreamt of and unhoped for reduction in suicide
rates is probably the result of more liberal treatment of young
people with S.S.R.I.'s, and it's suggestive that these drugs may
be responsible for saving a lot of lives," Dr. Shaffer said.
"The introduction of S.S.R.I.'s has been a revolution."
Yet most studies — including those recently reviewed by British
and American health regulators — have found that S.S.R.I.'s are
no more effective in fighting teenage depression than sugar
pills.
Even in adults, S.S.R.I.'s have been found to offer only modest
benefits. In about half of all adult tests, the drugs prove no
more effective than placebos. On average, they reduce symptoms
of depression by about 41 percent on a widely used scale, versus
a 31 percent reduction among those taking placebos, according to
a survey in 2000 of studies used by the F.D.A. in approving the
drugs.
Researchers, moreover, have not been able to analyze much of the
data on the drugs, because they have not been made public.
GlaxoSmithKline, for instance, has acknowledged that just one of
its nine studies of Paxil in children and adolescents has been
published — a study that made only passing mention of suicide
and concluded that the drug was effective against depression.
According to the F.D.A., the combined results of all nine trials
show that the drug is not effective against depression in
patients under 18. Of the S.S.R.I.'s, only Prozac is approved by
the F.D.A. to treat depression in children and teenagers,
although doctors also widely prescribe the others.
Dr. Graham Emslie, a professor of psychiatry at the University
of Texas Southwestern Medical Center who was a researcher in
four of GlaxoSmithKline's studies of Paxil, said he suspected
that the other studies went unpublished at least in part because
the results were unfavorable.
"Some of these studies were finished a couple of years ago," Dr.
Emslie said. "But negative trials tend not to get published."
Dr. Perera, the GlaxoSmithKline official, said that publishing
studies "takes time." He declined to say if the company would
seek to publish the eight Paxil studies that have not appeared
in journals.
According to Dr. Emslie, other companies have withheld negative
studies of S.S.R.I.'s. "I know of at least a half-dozen other
studies of antidepressant treatments in children and adolescents
that have been completed but as yet have not been published," he
said. "More than enough time has passed for these to be
published at least in abstract form." He refused to identify the
companies or the drugs involved because he, like other
researchers involved in similar research, has signed contracts
promising secrecy.
With negative results not disclosed, researchers and physicians
often believe that drugs are more effective and safer than they
actually are, according to Dr. Marcia Angell, a former editor of
The New England Journal of Medicine. "It changes the way
medicine is practiced," Dr. Angell said.
Back in 1991, in their presentation to the blue-ribbon committee
reviewing Prozac, Lilly scientists made much of the fact that
studies analyzing Zoloft and Paxil failed to show any link
between those drugs and an increase in suicides.
"There is simply no scientific evidence whatsoever, no
placebo-controlled double-blind study, that has established a
cause-and-effect relationship between antidepressant
pharmacotherapy of any class and suicidal acts or ideation,"
said Dr. Charles B. Nemeroff, a professor of psychiatry at Emory
University who worked as a consultant and spoke on behalf of
Lilly.
In an interview, Dr. Nemeroff said he believed that his
statement was accurate then and remains so, since he has not
seen any published study to contradict it.
The British and American regulators have reached a different
conclusion. And experts hired by lawyers suing the manufacturers
over claims that the drugs led to suicides question whether the
F.D.A. received a full picture of the available research in
1991.
For instance, F.D.A. procedures required Lilly to inform the
agency of any concerns about Prozac raised by other national
health authorities. But court records show that Lilly never told
the F.D.A. or the expert panel that German regulators initially
refused to approve Prozac's sale in 1985 because of concerns
over a link with suicide.
In their analysis of Lilly's data, the German authorities said
that Prozac seemed to have caused a substantial increase in
suicide among users, according to court records. Ultimately, the
Germans approved Prozac with a warning that physicians should
consider using sedatives for patients at risk of suicide.
No such warning is included in Prozac's label in the United
States, although the risk of suicidal thinking is listed among
the drug's side effects.
Gary Tollefson, a Lilly executive who spoke before the 1991
panel, was asked in a deposition why he did not tell the experts
about the German concerns.
"That was not a question I was asked," he said, according to
court records, "so I did not answer that question."
Documents brought to light in other cases suggest that Lilly
struggled for years to reconcile suicidal events among patients
taking Prozac in its trials. One memo shows that a top Lilly
executive asked the company's own researchers to record suicide
attempts as "overdose" and thoughts of suicide as "depression."
In another memo, a Lilly employee objected to those
instructions, making reference to the German health authority,
known by its initials as the B.G.A. "I do not think I could
explain to the B.G.A., a judge, to a reporter or even to my
family why we would do this especially on the sensitive issue of
suicide and suicidal ideation," he wrote.
In a recent statement, Lilly said: "There is no credible
scientific evidence that establishes a causal connection between
Prozac and violent or suicidal behavior. To the contrary,
scientific evidence shows that Prozac and other antidepressant
medications appear to reduce these behaviors."
Lilly representatives told the 1991 panel that the company had
put together a series of proposed studies to examine the suicide
issue and said one of the studies had already been started.
According to plaintiffs' lawyers, Lilly never completed the
study; Lilly declined to comment.
Were the F.D.A. to reconstitute the 1991 panel, its members
would again be presented with a confusing mix of data on the
issue — despite the passage of 16 years since Prozac's
introduction and the use by tens of millions of people of it and
other S.S.R.I.'s.
Under the circumstances, one member of the panel, Dr. Keh-Ming
Lin, a professor of psychiatry at the University of California
at Los Angeles, said the new information unearthed by regulators
might lead him to change his vote absolving S.S.R.I.'s of
suicide risk.
"If you have data that's worrisome, you tend to be
conservative," Dr. Lin said, "even when the question isn't
resolved."
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