5/9/2000 – Prozac Revisited

http://www.boston.com/dailyglobe2/128/nation/Prozac_revisited+
.shtml

Prozac revisited
As drug gets remade, concerns about suicides surface

By Leah R. Garnett, Globe Staff, 5/7/2000

Just as the 14-year patent on Prozac is about to expire and the
drug’s maker, Eli Lilly and Co., is preparing to launch a new
version, a body of evidence has come to light revealing the
antidepressant’s dark side.

The company’s internal documents, some dating to the
mid-1980s, as well as government applications and patents,
indicate that the pharmaceutical giant has known for years that
its best-selling drug could cause suicidal reactions in a small
but significant number of patients. The reports could become
critical as Lilly seeks government approval for its new Prozac.

Among the findings:

– Internal documents show that in 1990, Lilly scientists were
pressured by corporate executives to alter records on physician
experiences with Prozac, changing mentions of suicide attempt
to “overdose” and suicidal thoughts to “depression.”

– Three years before Prozac received approval by the US Food
and Drug Administration in late 1987, the German BGA, that
country’s FDA equivalent, had such serious reservations about
Prozac’s safety that it refused to approve the antidepressant
based on Lilly’s studies showing that previously nonsuicidal
patients who took the drug had a fivefold higher rate of suicides
and suicide attempts than those on older antidepressants, and
a threefold higher rate than those taking placebos.

– Lilly’s own figures, in reports made available to the Globe,
indicate that 1 in 100 previously nonsuicidal patients who took
the drug in early clinical trials developed a severe form of anxiety
and agitation called akathisia, causing them to attempt or
commit suicide during the studies.

– Though Lilly has steadfastly defended the drug’s safety and
downplayed studies linking Prozac to suicide, the patent for the
new Prozac, R-fluoxetine, expected to be marketed by Lilly
beginning in 2002, notes that the new version will not produce
several existing side effects including “akathisia, suicidal
thoughts, and self-mutilation,” which the patent calls “one of its
more significant side effects.”

– A McLean Hospital researcher and associate professor at
Harvard Medical School, Dr. Martin Teicher, whose early 1990s
studies linked Prozac to akathisia and suicide, is a co-inventor of
the new Prozac, which Lilly plans to market, along with Timothy J.
Barberich, the CEO of Sepracor Inc., a Marlborough drug
company, and James W. Young.

– A just-published book, “Prozac Backlash,” by a Cambridge
psychiatrist, Dr. Joseph Glenmullen, has drawn Lilly’s ire for
discussing Prozac’s link to suicide, tics, withdrawal symptoms,
and other side effects of Prozac and similar antidepressants.

Lilly officials continue to defend the drug’s effectiveness, saying
its track record is borne out by the fact it is still the most widely
prescribed drug of its kind. In a written statement, Jeff Newton, a
Lilly spokesman, said: “There is no credible evidence that
establishes a causal link between Prozac and violent or suicidal
behavior. There is, to the contrary, scientific evidence showing
that Prozac and medicines like it actually protect against such
behaviors.”

Using figures on Prozac both from Lilly and independent
research, however, Dr. David Healy, an expert on the brain’s
serotonin system and director of the North Wales Department of
Psychological Medicine at the University of Wales, estimated that
“probably 50,000 people have committed suicide on Prozac
since its launch, over and above the number who would have
done so if left untreated.”

Healy, meanwhile, is conducting a new study that he says is the
first of its kind, giving antidepressants to healthy people to study
possible links to suicide. The results are expected to be
published in June.

Prozac’s success is certainly unquestioned. The introduction of
the drug to the US market in the late 1980s changed the way
Americans viewed their most intimate emotions and limitations.
Billed as a wonder drug to combat depression by boosting
levels of the brain chemical serotonin, Prozac and others like it
were also said to remedy a host of human frailties from poor
self-esteem and concentration to fear of rejection.

By the end of last year, more than 35 million people worldwide
were using the drug, which provided Lilly with more than 25
percent of its $10 billion in 1999 revenue.

Yet the problems with Prozac were known even before it was
introduced to the US market. Figures in a 1984 Lilly document
indicated that akathisia, the severe agitation that can lead to
suicide, occurs in at least 1 percent of patients, a level
considered a “frequent” event, and as such must be disclosed in
a company’s product literature and package inserts. But there is
no such disclosure in Prozac’s US literature, and it is not clear
whether the FDA panel charged with approving Prozac simply
overlooked or did not have access to certain critical data of
Lilly’s.

As a result, researchers say that most US doctors do not know to
warn patients of the potentially dangerous effect which,
according to published literature on the topic, can be alleviated
with sedatives or by going off the drug.

German regulators, who eventually approved Prozac for use in
that country, require a warning label about the risk of suicide and
suggest the concurrent use of sedatives when necessary.

Akathisia is listed in Lilly’s US product literature, but as an
infrequent event in Prozac users. No mention is made of its
potential relationship to suicide.

A relationship, however, was found in a Globe search of US
patents. The patent for the new Prozac or R-fluoxetine (US Patent
no. 5,708,035), which Lilly will market after the existing patent
expires in 2001, contains a wealth of information about the
original Prozac. According to the patent, the new Prozac will
decrease side effects of the existing Prozac such as headaches,
nervousness, anxiety, and insomnia, as well as “inner
restlessness (akathisia), suicidal thoughts and self-mutilation” –
the same effect Lilly has contended has not occurred in any
substantial way in some 200 lawsuits against it over the past
decade. Most of the suits were settled out of court and the terms
kept confidential.

A 1990 communique

In an electronic communique obtained by author Glenmullen
dated Nov. 13, 1990, from Claude Bouchy, a Lilly employee in
Germany, to three Lilly corporate executives at the company’s
Indianapolis headquarters, Bouchy says he and a colleague
“have problems with the directions our safety people are getting
from the corporate group (Drug Epidemiology Unit) and
requesting that we change the identification of events as they are
reported by the physicians. . . . Our safety staff is requested to
change the event term `suicide attempt’ [as reported by the
physician] to `overdose.’ ”

Bouchy continued that “. . . it is requested that we change . . .
`suicidal ideation’ to `depression.’ ”

And then Bouchy makes an appeal to his US Lilly colleagues: “I
do not think I could explain to the BGA, to a judge, to a reporter or
even to my family why we would do this especially on the
sensitive issue of suicide and suicide ideation. At least not with
the explanations that have been given to our staff so far.”

Lilly has also aggressively sought to discredit researchers who
published data linking its product to suicide. One of its early
targets was Dr. Martin Teicher, an associate professor of
psychiatry at Harvard Medical School and a McLean Hospital
researcher, who wrote a crucial paper on the link between
suicide and Prozac in 1990; he found that 3.5 percent of patients
put on Prozac either attempt or commit suicide due to severe
agitation from akathisia. As a result of Lilly’s campaign, many in
the psychiatric community say they believe Teicher has
distanced himself from his original work. But in a rare interview
with the Globe, Teicher said that he stood by his work, and that
the ability of Prozac to induce suicide in a minority of patients “is
a real phenomenon.”

Teicher, Barberich, and Young filed their patent for the new
Prozac in August 1993, the same year Teicher published another
report, this one in the journal Drug Safety titled “Antidepressant
Drugs and the Emergence of Suicidal Tendencies.”

The paper was a direct challenge to data reported in the March
1991 issue of the Journal of Clinical Psychiatry by Drs. Maurizio
Fava and Jerrold Rosenbaum of Massachusetts General
Hospital. Their study found no significant difference in “suicidal
ideation” in patients treated with fluoxetine compared to those
receiving other antidepressants.

Teicher wrote in his 1993 paper that Fava and Rosenbaum’s
statistics were flawed. Using Fava and Rosenbaum’s data,
Teicher came to the opposite conclusion: namely, that patients
on Prozac were at least three times more likely to become
suicidal than those on older antidepressants.

The FDA came up with similar results even before Teicher
published his 1993 data. Dr. David Graham, chief of the FDA’s
Epidemiology Branch, wrote on Sept. 11, 1990, that Lilly’s data
on suicide and Prozac, as well as the Fava and Rosenbaum
study, were insufficient to prove that Prozac was safe. In an
internal FDA memo, Graham wrote: “Because of apparent
large-scale underreporting, the firm’s analysis cannot be
considered as proving that fluoxetine and violent behavior are
unrelated.”

“Prozac Backlash”

Now a decade later, Lilly has targeted Dr. Joseph Glenmullen,
whose book “Prozac Backlash” has apparently incensed Lilly
executives.

Glenmullen, a clinical instructor in psychiatry at Harvard Medical
School and a clinician at the Harvard University Health Services,
says he wrote the book because he was alarmed by the number
of patients who were reporting severe side effects from the
serotonin-boosting antidepressants including Prozac, Paxil,
Zoloft, and Luvox. “The two most upsetting side effects were
patients becoming suicidal on the drugs, and the development
of disfiguring facial tics,” he said in an interview.

After obtaining hundreds of pages of FDA documents through
the Freedom of Information Act, as well as internal Lilly memos
that are part of the public record in lawsuits filed against the drug
company, Glenmullen wrote that Lilly had tried to downplay side
effects of Prozac for years.

Lilly alerted newspapers and TV stations to the book and began
a campaign to discredit the author, saying that Harvard Medical
School professors were unfamiliar with his work and didn’t
recognize his name. Glenmullen, a graduate of Harvard Medical
School, is one of 415 clinical instructors in medicine at Harvard.

Blast from a critic

Chief among Glenmullen’s critics is Mass. General’s
Rosenbaum, a professor of psychiatry at Harvard Medical
School, who, in a written statement sent to the Globe calls
“Prozac Backlash” a “dishonest book” that is ” manipulative” and
“mischievous.”

But Rosenbaum’s objectivity has also been questioned. Not only
was his 1991 study on Prozac and suicide criticized by at least
two sets of researchers as well as the FDA, documents obtained
by the Globe show that Rosenbaum’s relationship to Lilly is a
cozy one: he has served as a Prozac researcher and sat on a
marketing advisory panel for Lilly before Prozac was launched.

When asked in an interview why he was speaking out against
Glenmullen’s book, Rosenbaum said that the suicide
controversy was “old news” and that the book presents the
information as new research. He noted that akathisia is “pretty
rare” and that “it doesn’t occur more than in people given a
placebo.”

But because there is no official reporting system for drug side
effects, no one knows how common drug side effects are, said
Larry Sasich, a research analyst at Public Citizen in Washington,
D.C.

“There is no active surveillance system to look at adverse
events,” he said. “Unless something very unfortunate happens
and a large number of people are harmed in a unique way, no
one is going to look at it; nobody ever puts two and two together.”

Sepracor’s patent

On April 12, the Federal Trade Commission opened the way for
Lilly to market Teicher’s, Barberich’s, and Young’s new Prozac,
for which Sepracor holds the patent. The new Prozac,
R-fluoxetine, is a modified form of an ingredient found in Prozac,
which, according to Sepracor, not only has fewer side effects but
more potential uses and benefits than the original.

In making the decision, the FTC rejected arguments from its
lawyers and the generic drug industry that the agreement unfairly
limits generic Prozac competition.

According to a Sepracor press release dated April 13, the
company will receive an upfront payment and license fee of $20
million from Lilly and an additional $70 million based on the
progression of the drug. Sepracor will receive royalties, and in
exchange, Lilly will get the exclusive world rights to R-fluoxetine
for all indications and uses. Lilly will be responsible for the
development of the drug, regulatory submissions, product
manufacturing, marketing and sales, according to the release.

Glenmullen wonders whether the new Prozac will, in fact, be little
more than an effort to prolong the life of a product with a
soon-to-expire patent.

Although it is touted as having fewer side effects, no one knows
what effects may surface once large numbers of people begin
taking it for months or years. In the epilogue to his book, he
simply says: “Like any new drug, it too will be an ongoing
experiment.”

This story ran on page A01 of the Boston Globe on 5/7/2000. ©
Copyright 2000 Globe Newspaper Company.

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