From: Adrienne
Subject: Data on Prozac

This article was originally published in the Guardian Weekend, 30
October, 1999, in South Africa.

THEY TOLD US IT WAS SAFE (Africa News Service)

Johannesburg (Mail and Guardian, November 5, 1999) - It was too good to be true. Prozac, taken by 38-million people worldwide, is not as harmless as we've been led to believe. Disturbing evidence has emerged, showing that Prozac can push some patients into so agitated a state of mind that they are a danger not only to themselves, but to others, too.

By Sarah Boseley

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. 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's been its biggest-selling pitch - Prozac is simple, legal and safe. GPs are handing it out to teenagers, even young children.

But since its launch in January 1988 in the United States 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 multinational 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 go on Prozac. Depressed people are often suicidal. Keep taking the tablets.

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.

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 Snr'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, director of the north Wales Department of Psychological 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 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 - about 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 Snr is typical of some people's catastrophic reaction to the drug, which hits the susceptible within days of starting on it. 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 to expand in 1986, it bought him out for big bucks. So he retired to Hawaii, where their son, Bill Jnr, had made his home with his wife and children.

But life soon began to jar for Bill Snr. 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 Snr walked away a couple of times, flying back to LA for some space.

Then he and June went to a marriage counsellor. They successfully sorted out their relationship. But in December 1992 Bill Snr began to have panic attacks. His doctor prescribed medication. Bill Snr did not like the idea of taking mind- altering drugs, but 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 Snr took his pills. The very next day he experienced the Prozac miracle. He felt wonderful. The clouds had cleared. Bill Snr called his doctor to tell him he felt 200% better. The next day, the doctor got another call. It was from Bill Jnr to tell him that a horrible change had come over his father. Bill Snr himself had demanded to be admitted to a psychiatric hospital. He spent a week in the Castle Medical Centre, on the neighbouring island of Oahu, where doctors continued to give him Prozac.

On March 3 1993, after 11 days on Prozac, Bill Snr went home at his own request. Bill Snr and June planned to go out whale- watching with Bill Jnr 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 Jnr and his sister, Susan, 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, Prozac was responsible.

In March this year, their suit against Eli Lilly finally came to trial in Honolulu. In the run-up to the trial, the Forsyth family's lawyers contacted Healy. 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. But this case was, to Healy, clearer than any of the previous ones. Bill Snr had no history of mental illness. He had never shown suicidal leanings. What had happened on the last night of his life was totally unexpected and out of character. Healy became 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 that Prozac is a useful antidepressant. 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.

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. Yet once Prozac was on the market, there was no warning to GPs that such action may 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. Lilly 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 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 Drug 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] 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 that November indicates that Lilly was keen to root out the word "suicide" from its database 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 almost impossible 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 don't 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."

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 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 about 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 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, including Prozac, and suicidality or violent behaviour".

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 - but none of those on the FDA panel would have been aware of the limitations of the Beasley study, because they would not have seen Lilly's internal documents.

The company's representative 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% 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. It 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, who is not around to see what effect it has on their behaviour. Nor is the GP warned that there may 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 about 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.

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, 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. They may well feel terrific - or they may be dead.

The Forsyths are going to appeal their case. Vickery, Warner and Company, 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 Cornwall smothered his wife, Sally, to death and then jumped off a 60m 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.

In fact, Healy says 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 problems they experience - perhaps because they do not understand what is happening to them - they may damage their chances of compensation if they later suffer harm.

Healy has identified problems with the licensing system, too, where patients' demands encourage manufacturers to concentrate on finding single "blockbuster" drugs that may make them millions, but 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 patients who go to see their GP tomorrow. They may be very miserable, and they may need help. But they are not so ill with depression that they want to kill themselves.

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 between life and death.