July 18, 2000
Once Again, Prozac Takes Center Stage, in Furor
By ERICA GOODE
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Naum Kazhdan/ The New York Times
At least two recently published books say that Prozac and related
antidepressants are often indiscriminately prescribed and pose the risk of
serious side effects, but critics of those views call them alarmist and
overblown.
Prozac has never been just any drug.
Soon after arriving on drugstore shelves 12 years ago, Eli Lilly’s
antidepressant transcended simple pilldom, becoming instead a cultural icon.
Hailed as a wonder drug one minute, cast as evil incarnate the next, the
green and white capsule has generated multitudes of lawsuits, and garnered
more attention than some presidential candidates.
Perhaps because Prozac treats the ills of the mind, not the complaints of the
body, it has also served as a kind of public Rorschach test, a screen upon
which Americans project deeply rooted attitudes about illness, character,
biology and free will.
So, perhaps predictably, as the drug edges into adolescence and Lilly’s
exclusive patent on the medication nears expiration, Prozac is once more
causing a stir.
More or less at the center of the newest squall are two psychiatrists, Dr.
Joseph Glenmullen, the author of a recently published book, “Prozac Backlash”
(Simon & Schuster), and Dr. David Healy, author of “The Antidepressant Era”
(Harvard University Press, 1998). They claim that Prozac and its chemical
cousins are often indiscriminately prescribed and have more serious and more
frequent side effects than the public is aware of or than the package
labeling indicates.
Many of their assertions are old ones, in particular the notion that the
drugs cause some people to become suicidal or violent, an accusation that
Lilly and other antidepressant manufacturers deny and that has so far failed
to persuade juries in product liability lawsuits.
But Dr. Glenmullen, who is on the staff of the Harvard University Health
Services, and Dr. Healy, a lecturer in psychological medicine at the
University of Wales College of Medicine, raise new fears. They suggest that
Prozac and similar drugs, like the antipsychotic medications of the 1950’s
and 1960’s, might pose a significant risk of neurological side effects, that
long-term use of the drugs might cause brain damage and that future
generations might look back on the antidepressants and other psychiatric
drugs, in Dr. Glenmullen’s words, “as a frightening human experiment.”
“Too many people have been lulled into thinking that they have no side
effects and no risk,” he said.
The contentions of Dr. Glenmullen, Dr. Healy and other critics, however, have
themselves drawn harsh criticism from scientists, psychiatric clinicians and
mental health groups, who view them as alarmist and overblown.
Some scientists whose studies are cited in “Prozac Backlash” to support its
thesis said that the author never contacted them about their work and they
strongly disagreed with his conclusions.
And many psychiatrists said they worried that the new dispute would
discourage people with depression from seeking needed treatment.
“Some of the statements that Glenmullen makes are simply outrageous,” said
Dr. Frederick Jacobsen, a psychopharmacologist in Washington. “He trashes any
benefit of the drugs and selectively quotes studies in a very biased way.”
The idea that Prozac and its later-arriving relatives are dangerous drugs
runs counter to the experience of most psychiatrists and researchers. They
see the medications — which enhance the availability in the brain of
serotonin, a neurotransmitter believed to be involved in depression — as
useful, and sometimes lifesaving, tools for treating a variety of psychiatric
disorders.
In their view, the antidepressants have both advantages and limitations. The
drugs, called selective serotonin reuptake inhibitors or S.S.R.I.’s, are far
less lethal in overdose than the older generation of so-called tricyclic
antidepressants, making them more difficult for depressed patients to use in
suicide attempts. And they lack some annoying side effects of the earlier
drugs, like dry mouth, constipation and weight gain.
Yet 30 percent to 40 percent of patients given the newer antidepressants
receive no benefit from them, a weakness they share with earlier medications.
Studies indicate the drugs may be less effective than tricyclics for severe
depression. And the medications, like all drugs, have side effects of their
own, including loss of libido and other sexual difficulties, which occur in
anywhere from 36 percent to 75 percent of patients, and a host of other,
mostly mild, adverse reactions.
Their long-term side effects, if any, are less clear. No scientist can offer
an ironclad guarantee that Prozac and its counterparts — or for that matter,
any other potent drugs — are absolutely safe when taken continuously for
long periods.
Yet what is known, scientists say, suggests that the medications are more
benign in their long-term effect on the brain than many other psychoactive
drugs. And 12 years of widespread use have convinced most researchers and
clinicians of the antidepressants’ basic safety.
“The S.S.R.I.’s are not innocuous,” said Dr. Matthew Rudorfer, associate
director for treatment research at the National Institute of Mental Health’s
Division of Services and Intervention Research, “and they should not be used
casually. But it’s a vast overinterpretation to say that they are dangerous
and should be avoided.”
The Arguments
A Calm Critique Amid Strong Claims
r. Glenmullen and Dr. Healy said they were not opposed to the use of Prozac
or similar drugs, and that they prescribed them regularly in their own
practices. But they deplore their use for people whose complaints are very
mild and they criticize physicians who place patients on the drugs for long
periods with little or no supervision, a trend that has increased under
managed care.
Lilly estimates that 38 million people worldwide have taken Prozac since it
was introduced in 1988. And 10.3 million new prescriptions for the drug were
written in 1999, says IMS Health, a market research firm.
“For people with only mild to moderate symptoms whose functioning is not
compromised,” Dr. Glenmullen said, alternative approaches, like psychotherapy
and exercise, “are preferable forms of treatment.”
Dr. Glenmullen also educates readers of his book about the withdrawal effects
— including nausea, vertigo, flu-like symptoms, mood swings and irritability
— that can result if newer antidepressants are stopped too abruptly.
(Prozac, which leaves the body more slowly than other S.S.R.I.’s, is an
exception). And both he and Dr. Healy criticize the pharmaceutical companies,
which they say influence medical research and often minimize adverse side
effects in an effort to make their products look good.
Yet it is difficult to find scientists or clinicians who support the more
extreme suppositions of Prozac’s critics.
Dr. Glenmullen and Dr. Healy, for example, argue that neurological side
effects — including muscle spasms, facial tics, Parkinson’s diseaselike
symptoms, extreme agitation and even tardive dyskinesia, a disabling movement
disorder — are more common in patients taking newer antidepressants than the
labeling on the drug packaging indicates, and that their occurrence augurs
serious problems to come.
Such side effects are frequently produced by older medications used to treat
psychosis. But Dr. Glenmullen said it took decades for doctors to recognize
the extent or severity of the reactions.
“Do we this time want to ignore the early warning signs of these effects with
serotonin boosters?” he asks in “Prozac Backlash.” “Even if disfiguring tic
disorders turn out to be infrequent, with tens of millions of people having
been on serotonin boosters, hundreds of thousands could be affected.”
But other scientists say it is misleading to compare antipsychotic drugs,
which directly act on the neurotransmitter dopamine, with the
antidepressants, which affect dopamine only indirectly.
“If S.S.R.I.’s do in fact cause tardive dyskinesialike syndromes, and that’s
far from proven,” said Dr. William Wirshing, a professor of psychiatry at the
University of California at Los Angeles and an expert on neurological
problems caused by antipsychotic drugs, “they do at a rate so low that it’s
indistinguishable from background noise in the untreated general population.”
Although some neurological side effects are reported in patients taking
Prozac and similar antidepressants, researchers and clinicians say that in
their experience the reactions are infrequent; some are so rare that many
psychiatrists never see them in years of practice. In many reported cases
patients have used other medications, making cause and effect difficult to
determine.
The Prognosis
Cause for Concern or Reassurance?
any scientists said that in their views “Prozac Backlash” also blurred
distinctions between newer antidepressants and many other types of drugs. In
a discussion of possible long-term effects of Prozac and similar drugs, for
example, Dr. Glenmullen drew analogies to cocaine and MDMA (the recreational
drug known as ecstasy), which are known to cause brain damage, and diet drugs
like Redux, which was pulled off the market in 1997.
Dr. Glenmullen said research was scant on how Prozac and other S.S.R.I.’s
affected nerve cells in the brain with long-term use, but he argued that
findings on the effects of ecstasy and other drugs offered reason for concern
about the antidepressants.
“Surely we already know enough to indicate these drugs should be prescribed
far more cautiously than they typically are today,” he wrote.
But Dr. George Ricaurte, an associate professor of psychiatry at Johns
Hopkins University and a leading expert on ecstasy’s effects on the brain,
said that MDMA and newer antidepressants “are two entirely different classes
of drugs.”
“The toxicity produced by MDMA is not produced by Prozac and related drugs,”
Dr. Ricaurte said. “Quite the contrary, they prevent the toxicity of MDMA and
related drugs.”
Dr. Efrain Azmitia, a professor of biology and psychiatry at New York
University and an authority on serotonin, said he regarded the newer
antidepressants as “remarkably effective and in a way, remarkably safe,”
because unlike many drugs their mechanism of action had “a more physiological
flavor, more in harmony with the body’s natural rhythms,” offering the
possibility that “you’re not going to all of a sudden see something appear
that you didn’t see at two years.”
Dr. Glenmullen, asked about other scientists’ disparate views, said that in
his book, “I’m very careful to be really clear about when I’m talking about
S.S.R.I.’s versus other classes of drugs” and his point was that “we badly
need more research.”
The Suicide Question
‘A Needle in a Haystack’
f all the issues raised by Prozac skeptics, the most difficult for many
people to sort out is the accusation that the drug is linked to suicide, an
association that began in 1990 when a Harvard University researcher, Dr.
Martin Teicher, reported on six patients who “developed intense, violent
suicidal preoccupation” shortly after starting Prozac.
Dr. Teicher’s report was followed by a few other case descriptions from other
researchers. Some scientists offered hypotheses about how such an effect, if
it existed, might occur.
One theory centered on an infrequent reaction to Prozac and other
medications, a state of agitation and restlessness known as akathisia. In
some cases, researchers suggested, akathisia may be so uncomfortable that it
sets off suicidal thoughts, or intensifies existing suicidal impulses.
Other investigators proposed that in rare cases the drugs might paradoxically
produce a drop in serotonin levels. Lowered serotonin levels have been
associated in some studies with suicide and other forms of violence.
In the public arena, the suicide question also created a commotion. Of the
more than 100 lawsuits filed against Lilly, many have been dismissed, and
some — the drug company will not say how many — have been settled out of
court. Two have come to trial, with both resulting in jury verdicts in favor
of the pharmaceutical company. In one case Lilly paid the plaintiffs an
undisclosed amount.
By the mid-1990’s, however, most scientists had lost interest in the issue.
Several larger studies — which compared Prozac to other antidepressants or
to dummy pills, including a reanalysis of Lilly’s clinical trial data —
concluded that subjects on Prozac showed no increase in suicidal acts or
feelings; some reported that the drug reduced suicide risk. In 1991, a Food
and Drug Administration advisory committee concluded that there was no
persuasive evidence for a suicide link, allaying many people’s fears.
The consensus of most researchers was that, in any case, disentangling the
effects of the antidepressants from the effects of depression itself, a
disease that has a high rate of suicide, was difficult or impossible.
“It would always be a needle in a haystack,” said Dr. Rudorfer, of the
National Institute of Mental Health.
For its part, Lilly said there was no data supporting the idea that Prozac
increased suicidal risk. “On the contrary,” said Dr. Steven Paul, a
psychiatrist who is a vice president at Lilly Research Laboratories, “all the
available data supports the fact that Prozac reduces suicidal risk in
depressed patients.”
In reviving the issue, Dr. Glenmullen and Dr. Healy, like earlier critics,
focus on Lilly’s role in lawsuits and research. They reprise, for instance,
accusations that the F.D.A.’s inquiry was tainted by some scientists’ drug
company ties. And they criticize the larger studies of Prozac and suicide,
citing problems in methodology, and pointing out that they were carried out
by scientists financed by Lilly or working for the company.
They also recycle excerpts from internal Lilly memos, retrieved by lawyers
for plaintiffs in earlier lawsuits.
Dr. Healy recently published a study in which 20 normal volunteers, who told
researchers they had no history of depression or other psychiatric problems,
were alternately given Zoloft, an S.S.R.I., and reboxetene, another
antidepressant that has not been approved for use in the United States. Two
of the volunteers, Dr. Healy reported, became acutely suicidal while taking
Zoloft.
Dr. Healy said that compared with the normal suicide rate in Great Britain,
the healthy volunteers on Zoloft showed a 2,000-fold increase in suicide
risk. He believes the same is true for other S.S.R.I.’s. “My estimates are
that Prozac alone has led to 25,000 people committing suicide” who would not
have otherwise, Dr. Healy said.
But the Zoloft study, published in a British journal, Primary Care
Psychiatry, is controversial. Critics said its methodology was flawed — for
example, they said, the study included no placebo control, the subjects were
employees of the hospital where Dr. Healy practiced, and no medical records
or other independent sources were evaluated to confirm the subjects’ reports
about their psychiatric histories.
To conclude that Zoloft made the subjects suicidal, , said Dr. Wirshing of
U.C.L.A., “is ludicrous.”
Celeste Torello, a spokeswoman for Pfizer Inc., which manufactures Zoloft,
Prozac’s closest competitor, said the drug’s “safety and efficacy has been
proven time and again, in more than 180 clinical trials involving more than
10,000 patients worldwide.”
Meanwhile, some researchers whose early reports on the suicide issue were
cited in “Prozac Backlash” said they did not agree with the way the issue was
characterized in the book.
One is Dr. Anthony Rothschild, a professor of psychiatry at the University of
Massachusetts in Worcester and the author of a 1991 report of three patients
who developed akathisia and became more suicidal on Prozac.
“Akathisia can occur,” Dr. Rothschild said, “and in some people, who have a
previous propensity to feel suicidal and are still suffering from depression,
this can sometimes push them over the edge. But is it common? No. Can it be
easily recognized and treated? Yes.”
Even Dr. Teicher, author of the original suicide report, said he viewed the
risk for suicide as something “that clinicians need to be aware of but it’s
generally not a huge problem.”
Dr. Teicher, who along with others holds the patent on R-fluoxetene, a
refined version of Prozac that Lilly has licensed and is testing in clinical
trials as a potential successor to the drug, speculated that patients who
became suicidal on Prozac and other drugs in the early 1990’s might have done
so as a result of the higher doses prescribed by physicians. Lilly’s
exclusive patent on Prozac expires in December 2003.
Dr. Glenmullen has written to the F.D.A. requesting that stronger warnings
about akathisia and suicides be added to labels for antidepressants.
But the federal agency, a spokesman said, is satisfied that current warning
labels, which mention both akathisia and suicidal thoughts as having been
reported since the drugs reached the market, are sufficient. The agency said
it had no plans to begin another official investigation into the issue,
although it would review any new data that emerged, as it does routinely on
topics of public concern.
In the end, the message for anyone contemplating taking Prozac, Zoloft,
Paxil, Luvox or other antidepressants, scientists said, may be simply that
drugs have side effects, and the decision to take medication always involves
the weighing of benefit against risk.
“No one should really be on any type of medication for long periods of time
unless they have to,” said Dr. Azmitia, of N.Y.U. “But some people really
can’t function unless they are on these drugs.”
