Re: Re: Freud and Science

[Doug Henwood <dhenwood@xxxxxxxxx>]

Louis Proyect wrote:

> beneficial effect of pills such as Prozac

The Guardian (London) - October 30, 1999

THEY SAID IT WAS SAFE: IT WAS TOO GOOD TO BE TRUE. PROZAC, THE
WONDERDRUG HAILED AS THE ANSWER TO THE WAR AGAINST DEPRESSION AND
TAKEN BY SOME 37 MILLION PEOPLE WORLDWIDE, IS NOT AS HARMLESS AS
WE'VE BEEN LED TO BELIEVE. DISTURBING EVIDENCE HAS NOW EMERGED

Prozac is the late 20th century's miracle drug - a medicine for a
world that wants simple answers to life's complexities. Happiness is
pill-shaped. Depression is soluble. No more worries. No more
wrestling with the gut-wrenching anxieties thrown up by the pressure
to succeed and the fact of our mortality. No more wondering whether
it would be nobler to end it all. Unsurprising, then, that Prozac has
been received across the globe with quasi-religious fervour. More
than 38 million people have taken it.

And, unlike the old prescription tranquillisers such as Valium and
Librium, Prozac is said to be safe. It is almost impossible to kill
yourself with an overdose. That has been its biggest-selling pitch -
Prozac is simple, legal and safe. GPs are handing it out to
teenagers, even to young children, in increasing numbers.

But since its launch in January 1988 in the US, and in the UK shortly
after, when Prozac was let loose on whole populations rather than on
selected patients in clinical trials, there has been a spate of
disturbing accounts of violence and suicide committed by people
prescribed the drug by their doctors. Some 200 cases have come to
court in the US. Victims and families of killers have sued the
multi-national Eli Lilly, manufacturers of the world's most
commercially successful drug. Until recently, not one case reached a
verdict. Either it was dropped, or Lilly settled out of court,
sometimes for millions of dollars - Lilly's defence has always been
the same: blame the disease, not the drug. Depressed people get put
on Prozac. Depressed people are often suicidal. Keep on taking the
tablets.

But earlier this year, for the first time, Lilly came up against a
family in the US who would not settle. The Forsyths wanted a hearing.
Internal documents belonging to Lilly were produced in court. And
although Lilly won the case - the jury decided it could not hold it
responsible for Bill Forsyth Sr's death - it may have lost the
argument, for those documents showed that Lilly knew as long as 20
years ago that Prozac can produce in some people a strange, agitated
state of mind that can trigger in them an unstoppable urge to commit
suicide or murder.

Dr David Healy, a leading UK psychiatrist in the field of
anti-depressant medicine and author of The Antidepressant Era, the
only comprehensive history of such drugs, believes that Lilly is
guilty of a failure to warn doctors and public of the terrible
potential consequences for some people of taking Prozac. 'Based on
published data and on Lilly's internal documents, the only reasonable
estimate for the number of people who have worldwide, because of
Prozac, tried to kill themselves since it was introduced would be a
quarter of a million - around 25,000 will have actually succeeded,'
says Healy.

Terrifying things happen to a number of people within the first few
weeks of taking the drug, says Healy. They become agitated, restless
and anxious. Out of the blue, and completely out of character, they
may try to kill themselves in extremely violent ways, and they may
try to take others with them.

What happened to Bill Forsyth Sr is typical of some people's
catastrophic reaction to the drug, which hits the susceptible within
days of starting on it. (The first Prozac case to come to litigation
concerned Joseph Wesbecker, a Louisville printer, who took several
automatic weapons to work one day and killed eight and injured 16 of
his colleagues before turning the gun on himself.) Forsyth was a man
of certainties. He was a go-getter, the sort of run-of-the-mill
success story that America rejoices in. For 40 years, he'd been in
the car business in California, land of the freeway, owning a
car-rental firm based at Los Angeles airport. When the airport needed
his space for expansion in 1986, it bought him out for big bucks.

So Bill retired. He had plenty of money to spend on the leisure and
pleasure he'd never had time to enjoy. He and his wife spent four
more years in California, where they had brought up their two
children, Susan and Bill Jr. Then they moved to Hawaii, where their
son had made his home with his wife and children. But life soon began
to jar for Bill Sr. He found it hard to reconcile the simple,
hedonistic life of his son with his own dogged, lifetime pursuit of
ambition and material goals. And he and June, his wife of 37 years,
were falling out. They had built themselves a luxurious house on
Maui, but were under each other's feet, unused to being constantly
together. Bill walked away a couple of times, flying back to LA for
some space. Then he and June went to a marriage-guidance counsellor.
They successfully sorted out their relationship.

But in December 1992 Bill began to have panic attacks. His doctor
prescribed medication, which worried him a little: many years
earlier, the self-imposed pressures of his business had led to heavy
drinking, and he had not touched a drop for a very long time, so did
not like the idea of taking mind-altering drugs. Still, he was the
sort of man who wanted to do what the doctor told him, so he took his
medicine. But it didn't work. Let's try something else, said the
doctor. A new drug, Prozac. Obediently, Bill Sr took his pills. The
very next day he experienced the Prozac miracle. He felt wonderful.
The clouds had cleared. Bill called his doctor to tell him he felt
200% better.

The next day, the doctor got another call. It was from Bill Jr to
tell him that a horrible change had come over his father. Bill Sr
himself, who had rarely been in hospital in his life, had urgently
demanded to be admitted to a psychiatric hospital. He spent a week in
the Castle Medical Center, on the neighbouring island of Oahu, where
doctors continued to give him Prozac. On March 3 1993, after 11 days
on Prozac, Bill Sr went home at his own request. Bill Jr went round
for dinner. Bill Sr and June planned to go out whale-watching with
their son the next day. When they didn't turn up as arranged, he went
to the house. He found a scene of carnage: during the night or early
in the morning, his father had stabbed his mother 15 times and had
then placed a serrated kitchen knife on a stool and impaled himself
on it.

Bill Jr and Susan and were devastated and disbelieving - never in a
thousand years would they have guessed that their father might one
day murder their mother and then kill himself in so violent a
fashion. As far as they were concerned, there could be only one
answer - that Prozac was responsible.

In March this year, their suit against Eli Lilly finally came to
trial in Honolulu, Hawaii. In the run-up to the trial, the Forsyth
family's lawyers contacted Dr Healy at his home in Bangor, north
Wales. It was not the first time he had been asked to look at a case
against Lilly that alleged Prozac had caused balanced individuals
with minor depression to become suicidal killers. Every time, Healy,
who is director of the north Wales department of psychological
medicine, had come to the conclusion that there was no case to
answer, and at first wasn't inclined to wade through the Forsyth
papers. But he was about to fly to the US, anyway, so he relented.
Okay, he told the lawyers, let me see the files when I get there.

Several boxes of documents arrived in his hotel room. This case was,
to Healy, clearer than any of the previous ones. Bill Sr had no
history of mental illness. He had never shown any suicidal leanings.
What had happened on the last night of his life was totally
unexpected and out of character. Nobody would have predicted it, and
nobody could understand it. Healy became increasingly convinced that
Prozac had sent Forsyth into a homicidal, suicidal frenzy. He agreed
to become an expert witness for the family against Eli Lilly.

What Healy has learned during the litigation has surprised and
worried him. He believes, as he always has, that Prozac is a useful
anti-depressant. But there is now a mound of evidence that, in a
minority of cases, it induces a strange and disturbing state of mind
that can lead to violence and suicide. This state of mind is a
recognised psychiatric phenomenon, called akathisia. Akathisia was
described by the Forsyths' attorney, Andy Vickery, as a sort of
jitteriness or feeling 'wired', like the effects of drinking too much
strong black coffee. But on Prozac, the experience can be far more
severe, sometimes leading to an inability to keep still and to
restless pacing up and down.

Vickery told the jury that it was like the onset of seasickness
within hours or days of feeling fantastic at the start of a cruise.
You try to ignore it. You tell people you feel fine, hoping it will
go away. You can't stay in one place - you go outside for air, then
back in to try to keep still. Then, just when you think it's over,
you race to the side and retch your guts up.

Akathisia caused by antipsychotic drugs has long been recognised as
leading to suicidal and homicidal-suicidal feelings. But
antipsychotics such as chlorpromazine, while sometimes inducing
suicidal feelings, take away the will to do anything about it. Never
- before Prozac - had it been associated with antidepressants, which
apply no such brakes on action. So doctors would not expect to see
it. Lilly had issued no warnings that it could occur, even though
akathisia had been spotted in some patients during the clinical
trials before Prozac was given its licence.

Lilly's own internal documents show it was identified as early as
1978. On August 2 of that year, when only three trials were under
way, minutes of a meeting of the Fluoxetine (Prozac) Project Team run
thus: 'There have been a fairly large number of reports of adverse
reactions . . . Another depressed patient developed psychosis . . .
Akathisia and restlessness were reported in some patients.' A similar
meeting 10 days earlier had noted that 'some patients have converted
from severe depression to agitation within a few days; in one case
the agitation was marked and the patient had to be taken off [the]
drug.'

The minutes further state that 'in future studies the use of
benzodiazepines to control the agitation will be permitted'. So, from
that point on, Lilly's trial subjects would be put on tranquillisers
to get them over the akathisia experienced by some in the early days
on the drug. Yet once Prozac was on the market, there was no warning
to doctors that such action might be necessary.

Those who developed akathisia or who had any suicidal tendencies were
excluded from the trial data on the basis that they would otherwise
obscure the results of the drug's success in treating depression. Yet
the German licensing authority, the Bundes Gesundheit Amt (BGA), on
scrutinising the results, expressed concerns about the drug's safety.
On May 25, 1984, according to Lilly's internal documents, a letter
from the BGA stated: 'During the treatment with the preparation
[Prozac], 16 suicide attempts were made, two of these with success.
As patients with a risk of suicide were excluded from the studies, it
is probable that this high proportion can be attributed to an action
of the preparation [Prozac].'

In January 1985, the Germans told Lilly that they would not license
the drug, giving 'suicidal risk' as one of the reasons for their
decision. Lilly's scientists continued trying to persuade the BGA to
grant a licence, but focused most of their efforts on the US. By
August 1989, it was clear to Lilly that the BGA would demand that
Prozac carry a warning to GPs to the effect that they should be aware
of the risk of suicide unless they gave patients sedation along with
their Prozac. Such a warning, stating that there was a 'risk of
suicide', finally went on the German package insert in 1992. It goes
on: 'For his/her own safety, the patient must be sufficiently
observed, until the antidepressive effect of Fluctin [Prozac] sets
in. Taking an additional sedative may be necessary.'

During the licensing process in the US, however, Lilly did not tell
the Food and Drugs Administration (FDA) of the German concerns.
Indeed, the firm's papers disclose a long and successful battle
against the idea that Prozac could induce violence or suicide. They
suggest that Lilly had an explicit strategy to blame the disease and
not the drug, and that some of Lilly's own scientists had
reservations about this.

One of them, John Heiligenstein, wrote in an internal memo on
September 14, 1990: 'We feel caution should be exercised in a
statement that 'suicidality and hostile acts in patients taking
Prozac reflect the patient's disorder and not a causal relationship
to Prozac'. Post-marketing reports [reports from GPs of suicides and
violence in patients on the drug] are increasingly fuzzy and we have
assigned, 'Yes, reasonably related', on several reports.'

This memo was written two years after Prozac was granted a licence in
the US, and just months after the most dangerous challenge to Lilly's
position so far. Earlier in 1990, Martin Teicher, Jonathan Cole and
Carol Glod, who were linked to Harvard University, published a study
of six patients on Prozac. They had a history of depression, but all,
while on the drug, became violently suicidal in a way that surprised
themselves and their doctors. The report noted that suicidal thoughts
occurred within days or weeks of going on Prozac, or of having the
dosage increased beyond a certain level, and that such thoughts
disappeared when the patient stopped taking the drug. But Lilly
insisted that Prozac did not cause akathisia. For good measure, the
company asserted that the link between akathisia and suicide is
questionable.

Lilly's internal documents of the time show that it was going through
a difficult period. Some of the public criticism of its blockbuster
drug was coming from the UK. 'Anything that happens in the UK can
threaten this drug [Prozac] in the US and worldwide,' ran an internal
memo from Leigh Thompson, one of Lilly's chief scientists. 'We are
now expending enormous efforts fending off attacks because of 1)
relationship to murder and 2) inducing suicidal ideation [suicidal
behaviour].'

Another memo from Thompson ran: 'I am concerned about reports I get
re UK attitude toward Prozac safety. Leber [Dr Paul Leber of the FDA]
suggested a few minutes ago we use CSM [the British Committee on
Safety of Medicines] database to compare Prozac aggression and
suicidal ideation with other antidepressants in the UK. Although he
is a fan of Prozac and believes a lot of this is garbage, he is
clearly a political creature and will have to respond to pressures. I
hope Patrick [probably a Lilly employee, but not identified fully in
the memo] realises that Lilly can go down the tubes if we lose
Prozac, and just one event in the UK can cost us that.'

This was how high the stakes had become. Without Prozac, Lilly could
'go down the tubes'. A memo from the German office to Lilly's US
headquarters in that November indicates that Lilly was keen to root
out the word 'suicide' altogether from its database record of
side-effects experienced by patients on the drug: Claude Bouchy and
Hans Weber in Germany were alarmed by suggestions from their US
superiors that, when GPs reported a suicide attempt on Prozac to
them, they should record it as 'overdose' (even though it is not
possible to kill yourself by overdosing on Prozac), and that a GP's
report of 'suicidal ideation' should be recorded as 'depression' -
'Hans has medical problems with these directions and I have great
concerns about it,' runs a memo from Bouchy to Thompson. '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.'

Something had to be done. Lilly finally agreed to undertake the study
suggested by the FDA, and look at the suicide rate among UK patients
on Prozac, but it didn't. Instead, the company put together a
'meta-analysis' from the clinical trials before the drug had been
licensed (meta-analysis pools all the data from all available trials,
and looks for trends from that very large sample of patients). The
object was to find out whether more people on Prozac had become
suicidal than those given a placebo or other treatment without
knowing it. Lilly's own scientists, led by Charles Beasley, did the
work.

Beasley's study was rejected by the New England Journal of Medicine,
but the British Medical Journal accepted and published it in 1991. It
had 'the appearance of scientific rigour', says Dr Healy, but it is
clear, he says, in the light of the documents that emerged in the
Forsyth case, that the so-called meta-analysis had included only
3,065 patients out of around 27,000 involved in the trials and that
it had also included data that the FDA had rejected during licensing.
Among those excluded from Lilly's study were the 5% of patients who
had shown akathisia-like symptoms during the clinical trials and had
dropped out, and also the 13 or 15 suicides - 'given the populations
being studied and the numbers involved, there should have been no
suicides', says Dr Healy. Nor was there any mention of the fact that
a considerable number of patients had been put on benzodiazepines to
suppress the very problem that Lilly was claiming did not occur. Nor
did the study mention any suicides since the licensing of the drug,
which by that time numbered some 198 in the US and 94 elsewhere.

On the basis of this material, and on Lilly's constant reiteration
that depression and not the drug causes suicide, the FDA's
psychopharmacological drugs advisory committee decided in September
1991 that there was 'no credible evidence of a causal link between
the use of antidepressant drugs, includ ing Prozac, and suicidality
or violent behaviour'.

The FDA voted six-three against demanding a warning on the label, but
agreed that 'more research is needed to further explore all the
potential implications of these reports, not only for Prozac but for
other antidepressants as well. Some members also expressed concern
that some physicians may fail to properly monitor patients being
treated with antidepressants.' However, none of those on the panel
would have been aware of the limi-tations of the Beasley study,
because they would not have seen Lilly's internal documents.

It is this FDA conclusion from nine years ago that Lilly now cites
every time questions are raised about suicides, homicides and its
best-selling drug. The company's spokesman in Indianapolis told me :
'That is more important than an attorney's selective manipulation of
data. You have to take a look at the patient population. In people
with depression there is probably a 15 per cent suicide rate. There
is no evidence that Prozac causes suicide.'

Lilly adds to this the evidence from three small studies that, Healy
argues, are flawed. One, for instance, was a study of 654 anxious -
not depressed - patients, of whom only 187 were on Prozac. According
to Lilly's argument, none of these patients should have committed
suicide, because they were not depressed - and yet one of those on
Prozac did.

The agitated state of mind that Prozac brings on in a minority of
people who take it (perhaps one in four) might not have mattered if
it had been aimed only at the seriously clinically depressed in
hospital, where they would be regularly observed and sedated if they
showed signs of acute anxiety. But Prozac is not that sort of drug.
Prozac has always been aimed at the general population - those with a
less significant depression or anxiety which did not wreck their
lives but simply made them more difficult. These people get Prozac
from their GP. And that GP is not around to see what effect the drug
has on their behaviour. Nor is the GP warned that there might be a
problem.

In 1995, new evidence of Prozac's dangers emerged from just the type
of study that the FDA had requested years earlier, although it was
not carried out for that specific purpose. A Boston-based scientist,
Herschel Jick, carried out a study of suicides in the UK among people
who had been prescribed antidepressants by their GP. Jick compared
the suicide rates on 10 different antidepressants, and found that far
more killed themselves on Prozac than on other drugs.

Jick's study found that there were 187 suicides per 100,000 depressed
patients per year on Prozac. Lilly argues, however, that suicide
rates among people with depression run at about 600 per 100,000. But
those figures, says Healy, apply only to hospital patients with acute
depression. Among the depressed population in the community, the
published studies show the suicide rate is only around 30 per 100,000.

So, on those figures, 157 people prescribed Prozac by their GP out of
every 100,000 will kill themselves because of it. In fact, says
Healy, the likelihood of someone committing suicide on Prozac
prescribed by their GP during their first month of treatment is 10
times greater than if they were untreated, which is a level of risk
approaching that of smokers' likelihood of developing lung cancer.

Lilly says that 38 million people worldwide have taken Prozac. Given
that number, says Healy, 25,000 will have killed themselves and a
quarter of a million will have tried. In the UK, between 1994 and
1999, at least one million people have taken Prozac, which, claims
Healy, must mean 1,000 UK suicides and 10,000 attempts.

Healy does not want to see Prozac withdrawn, however. He wants,
instead, to see a clear warning on the label, so that GPs will know
they must keep a close watch on their patients for the first few
weeks of treatment, and to give patients a sedative if they appear
agitated. Left to themselves, with no doctor to please, patients
suffering from akathisia will usually give up on the drug - they just
feel too bad to continue - but Lilly's guide to the treatment, and
the standard GP advice, is to carry on taking the medicine. Once a
patient is over the bad patch, it is argued, they will feel terrific
(see box opposite). They may well feel terrific - or they may be dead.

Teenagers in the UK are now being given Prozac by their doctors on
the assumption that it is safe. They will not necessarily be closely
monitored, let alone taken off it if they start getting agitated. 'I
have been notified of four or five cases of kids in their teens who
have committed suicide by hanging themselves within weeks of going on
Prozac - one of them only 13,' said Healy. 'It used to be almost
unheard of for teenagers to kill themselves. They might make gestures
and might overdose, but they usually do not die.'

The Forsyths are going to appeal their case. Vickery, Warner and Co,
of Houston, Texas, the law firm that represented the family, cannot
believe that they lost. 'I was shocked and disappointed for months,'
says Andy Vickery. 'In the final argument, I told the jury that their
verdict could save lives. I'm now representing families of people who
killed themselves after that verdict.'

The arguments Vickery made in Honolulu may now be used in the UK:
proceedings have recently been issued in the first British Prozac
case. In 1996, 10 days after starting on Prozac, Reginald Payne from
Wadebridge in Cornwall smothered his wife, Sally, to death and then
jumped off a 200ft cliff.

If Healy is right, and so many people have died for want of a warning
to GPs who prescribe Prozac, it is an indictment not just of Eli
Lilly but of the clinical trials system itself. In spite of all the
work involved in these trials, all the volunteers who take part in
the hope of helping themselves and benefiting mankind, and all the
millions that are spent, they prove only that a drug will not
obviously harm you and that it has some effect on the medical
condition. They do not satisfactorily detect the side-effects that
patients may go on to suffer. And once the drug is licensed, the
reporting of side-effects by GPs who hear about them from their
patients is notoriously unreliable.

The difficulty with a drug such as Prozac, which works on the mind,
is that patients may not spontaneously report problems. During the
trials, for instance, only 5% reported sexual problems - it is now
known that half of those on the drug may experience changes in sexual
functioning. And how are they supposed to report a side-effect, such
as akathisia, that they've probably never heard of?

The answer to this side-effects problem, says Healy, is to draw up a
checklist. Patients in trials should be asked if they are suffering
from any of a range of possible side-effects. One study has shown
that patients who are asked only to tell the doctor if they have a
problem may underestimate the side-effects they suffer by a factor of
six to one. 'As things stand at present,' says Healy, 'individuals
entering a company-sponsored trial risk rendering a disservice both
to themselves, to their fellow patients and to the community at
large. They need, therefore, to consider before entering such trials.
Their relatives and friends need to consider before letting them
enter such trials.'

In fact, Healy maintains, patients taking part in clinical trials
where the side-effects are not recorded through a checklist may be
putting themselves in legal jeopardy. If they fail to tell the doctor
of any problems they experience - perhaps because they do not
understand what is happening to them at the time - they may damage
their chances of any compensation if they later suffer harm.

Healy would like the UK ethics committees, which have to approve all
trial protocols, to insist on the checklist approach to the reporting
of side-effects. If that were to happen in the UK, he argues, the
practice would inevitably spread worldwide, since virtually all
trials are now international.

Healy has identified other problems with the licensing system, too,
where patients' demands encourage manufacturers to concentrate on
finding single 'blockbuster' drugs that may make them millions, but
that may equally break a company. The stakes are that high. So high,
in fact, that Healy wonders about the legal advice companies are
getting - several tobacco corporations, for example, have been
advised by their lawyers not to do research into the dangers of
cigarettes for fear of increasing their legal liability.

Whatever is going on inside the huge pharmaceutical multinationals
today, all that really matters is the depressed patient who goes to
see his GP tomorrow. He may be very miserable, and he may need help.
He may think that his job or his marriage or both, are on the skids.
But he is not so ill with depression that he wants to kill himself.
Prozac may well be the answer, but it may also be a final solution. A
warning and some close watching could make all the difference to him
between life and death