8/7/2003
Debate Resumes on the Safety of Depression's Wonder Drugs

GARDINER HARRIS
NEW YORK TIMES



After a decade of lies, deception, and cover-up of evidence linking
antidepression drugs (such as, Prozac, Paxil, Zoloft) to acts of suicide

previously non-suicidal people (children and adults, some of who were
depressed, others not) a front page article in The New York Times has
finally opened the much needed public debate in the United States.

The Times reveals that in light of public revelations in Great Britain

the high suicide risk for children who were given Paxil in clinical

seven members of an expert panel convened by the FDA in 1991 said they

now reconsider their recommendation exonerating these drugs from a link to
suicide.

An eye witness who testified before the FDA panel in 1991 recalled "the

company representatives - a huge panel of dark suits sitting right up

next to the panel breathing down their necks and laughing a jeering at

who were testifying to the horrors their families had experienced "The

horrifying reports one could imagine were being made by family members and
they were laughing at them. I could not believe my eyes or ears!" Dr.

Teicher was invited to present information about the problems with these
drugs he was cut off immediately and not allowed to speak. It was such an
obvious sham.

Concern about the link between SSRIs and suicide has persisted ever since
these drugs were first tested in clinical trials on healthy adults. When

German regulatory agency (BGA) examined the Prozac clinical trial data, it
concluded that the data showed insufficient evidence of the drug,s

for depression, while the evidence did show increased agitation before any
elevating mood effect resulting in "an increased risk of suicide.?

disclosed during court proceedings reveal that FDA officials knew this
information--as it had been submitted by Eli Lilly in 1987. But this vital
information was concealed from doctors and patients alike~until it was
uncovered during litigation.

These life-threatening risks were kept secret until Dr. David Healy, an
acknowledged expert on psychopharmacology, opened the current debate by
bringing to light heretofore concealed evidence that validated concerns
about the safety of SSRIs in publications, at professional meetings, at

Royal College of Psychiatry, in US courts, and by alerting the British
health authorities, and the free press.

Several published analyses of FDA data by other independent analysts have
clearly demonstrated that there exists no credible evidence from

clinical trials that these drugs are any more effective than placebo~only
that they produce an effect. For that reason, the risks posed by these

must be fully justified. Contrary to denials by the drug makers,
psychiatrists who are paid by these companies, and until now, denial by

officials, there IS credible evidence that Paxil, Prozac, Zoloft and the
other SSRIs cause suicide and / or aggression. As the powerful

reports by the BBC revealed that there is also credible evidence of severe
withdrawal symptoms--a sign of addiction.

In light of the public revelations about Paxil by the BBC and then by the
British health authority~that in nine Paxil trials in which 1,000 children
participated, those taking Paxil were 3.2 times as likely to have suicidal
thoughts or suicide attempts than children who were on placebo~the FDA is
reported to be "considering whether to impose new restrictions on the use

the anti-depressants.?

FDA has, until now, listened only to drug manufacturers and
psychopharmacologists whose financial ties to those companies compromise
their objectivity if not their integrity. The Alliance for Human Research
Protection is an independent watchdog organization with absolutely no ties
to the drug industry. We hereby offer to meet with FDA officials to help
them arrive at a decision that is based on complete, credible, unbiased,
unmanipulated empirical evidence. Until now, FDA has evaded such

of all the data from these drugs, clinical trials. Is seems to us that the
focus of FDA,s review should be to assess the controlled clinical trial

in order to determine what would have the suicide rate been for these
patients if left untreated.

AHRP has persuaded Dr. Healy to attend such a meeting that AHRP hopes to
arrange with FDA officials. In 1997, as Secretary of the British

for Psychopharmacology, Dr. David Healy organized, chaired and wrote up

recommendations from an International Roundtable Meeting for the British
Association for Psychopharmacology on the use of psychotropic drugs in
children. This meeting involved senior regulators from the US and Europe

well as professors of child psychiatry from a number of European

North America and the UK, and was aimed at establishing what principles
might underpin the safe and effective use of psychotropic drugs for
children.

AHRP calls upon Congress to hold hearings requiring drug manufacturers,

psychiatric establishment, and FDA officials to answer what they knew

SSRI induced suicides in children and healthy adults? When they knew it?

why they have deceived the public about the safety of these drugs and

effectiveness?

They will have to answer why--inasmuch as they knew about the drugs'
hazards--they have encouraged doctors (who were not privy to the hidden
information) to prescribe the drugs for thousands of children?

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP) http://www.ahrp.org
Contact: Vera Hassner Sharav
Tel: 212-595-8974
e-mail:

and Drug Administration ~ that unpublished studies about Paxil show that

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.

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

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

could have caused.

Almost no one suggests that Prozac, Zoloft, Paxil and their cousins are

safe for the vast majority of adults, although studies have shown them to

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

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

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

these drugs and suicide," said Dr. Jeffrey A. Lieberman, a professor of
psychiatry and pharmacology at the University of North Carolina and a

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

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

year, have treaded carefully in responding to the warnings. Without
criticizing the regulators, they maintain that there is no proof that

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

S.S.R.I. prescriptions, and companies that track the industry have

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

they're safe drugs."

But the warnings are beginning to seep into doctors' awareness.

officials, for example, last month dropped Paxil from their list of

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

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

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

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

"I feel vindicated," said Joseph Glenmullen, author of "Prozac Backlash,"

fierce critique of antidepressants. "These companies have vehemently

this side effect for over a decade, and now their own data indicate

a significant risk."

The British regulators said that their analysis of the nine studies of

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

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

said Dr. Riddle, who in 1991 conducted one of the first studies of the

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

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.

about half of all adult tests, the drugs prove no more effective than
placebos. On average, they reduce symptoms of depression by about 41

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

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

of all nine trials show that the drug is not effective against depression

patients under 18. Of the S.S.R.I.'s, only Prozac is approved by the

to treat depression in children and teenagers, although doctors also

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

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

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

companies or the drugs involved because he, like other researchers

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

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

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.

experts hired by lawyers suing the manufacturers over claims that the

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

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

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

of suicide.

No such warning is included in Prozac's label in the United States,

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

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

"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

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

or even to my family why we would do this especially on the sensitive issu

of suicide and suicidal ideation," he wrote.

In a recent statement, Lilly said: "There is no credible scientific

that establishes a causal connection between Prozac and violent or

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

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

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,

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."