The Great Prozac Conspiracy

After 20 years of these so-called miracle antidepressants, psychiatrists are shocked to discover that drug companies withheld information about the risks of this class of drugs–and with the tacit approval of the drug regulators.

It all started so promisingly, when drugs like Prozac first came on the market in the 1980s. Here at last, we were told, was a new class of antidepressants that would transform the world of psychiatry.

Out would go the old ‘dirty’ psychiatric drugs of the 1950s, and in would come a set of drugs honed by science to target the biochemical core of depression in the brain.

These new drugs had a very scientific-sounding name—‘selective serotonin reuptake inhibitors’—which neatly morphed into the catchy acronym ‘SSRIs’. They are among the most successfully marketed drugs in history, so much so that the brand leader Prozac is almost a synonym for antidepressants, just like Hoover is for vacuum cleaners.

But now, some two decades later, the world of psychiatry has finally discovered it has been largely taken for a ride with SSRIs, by both drug companies and lax regulators.

‘Miracle’ science

In the brain, messages are passed between brain cells (neurones) across a tiny gap called a ‘synapse’. This gap is filled with chemicals, which have the job of controlling the communication between brain cells, transmitting information from one neurone to the other. Hence, these chemicals are called ‘neurotransmitters’. When one neurone communicates with its neighbour, it floods the synapse with a cocktail of neurotransmitters, one of which is serotonin.

By the 1970s, it had been discovered that some prescription drugs can cause depression as a side-effect, a problem traced to low brain levels of serotonin. It was then argued that, if a way could be found to increase serotonin in the brain, it would reduce depression.

It’s already known that the brain naturally conserves neurotransmitters by allowing the transmitting cell to reabsorb them from the synapse (a process that is called reuptake). So, if a way can be found to stop (or inhibit) this reuptake, the synapse would remain constantly bathed in neurotransmitters. But only one neurotransmitter—serotonin—is involved in depression, which means that only serotonin needs to be selectively isolated from the rest of the neurotransmitter cocktail.

So, in the mid-1970s, the pharmaceutical companies set themselves the task of finding a drug that would select out serotonin, and inhibit its reabsorption by the transmitting neurones. Ten years later, the family of SSRIs was created.

The first SSRI appeared in the mid-1980s from the Swedish pharma company Astra. The drug’s chemical name was zimelidine, but it was quickly withdrawn from the market when patients developed Guillain–Barré syndrome (a serious auto-immune condition involving damage to the peripheral nerves). Soon after-wards, a second SSRI, a French drug called indalpine, was also stopped after it was found to damage blood cells.

These straws in the wind didn’t deter other drug companies, however —although the SSRI’s hoped-for lack of side-effects had been intended to be a major part of their sales pitch.

The first SSRI to come to market was fluvoxamine (see box, page 8),
but its manufacturer Solvay Pharmaceutical, based in Georgia, lacked marketing clout, making its launch a bit of a damp squib.

It took the marketing power wielded by the giant US (and international) drug company Eli Lilly to collar most of the SSRI public relations when it launched fluoxetine in 1987, under the memorable trade-name Prozac. Newspapers were quick to swallow the company’s sales pitch, with headlines describing Prozac as a “happiness pill”. Even normally cynical journalists described Prozac as a valuable, quick, emotional fix, and a panacea for the stresses of the 20th century.

But the marketing dream soon turned into a PR nightmare as patients began to complain of unpleasant side-effects such as nausea, sexual dysfunction, insomnia and gastrointestinal bleeding. Worse, Prozac some-times caused violent, irrational behaviour. In one infamous case, a middle-aged factory worker became homicidal while taking Prozac, killing five people and wounding 12 others at his workplace.

In another example of horrific behaviour as a result of taking this drug, a female patient attacked her mother by biting her so viciously that she managed to rip away 20 chunks of her mother’s flesh. Eli Lilly was ordered to pay substantial damages.

After SmithKline Beecham (now GlaxoSmithKline or GSK) weighed in with their own SSRI, Seroxat (paroxetine), similar side-effects were seen with their drug, too. Even doctors began to express some concerns. “Physicians are seeing long-term side-effects from SSRIs far in excess of what was expected from the clinical trial data,” Dr Norman Sussman, a psychiatrist at New York University Medical Hospital, told the press in 1998 (Clin Psychiatr News, 1998; 26: 1).

Within a few years, Seroxat was following Prozac into the courts. In June 2001, GSK was ordered to pay $6.4m to the family of Donald Schell, who, after just two days on Seroxat, killed his wife, daughter, grand-daughter, and finally himself. Although GSK tried to claim that the drug wasn’t to blame, the British expert witness Dr David Healy, of Bangor University in North Wales, told the court he had uncovered early Smith-Kline Beecham documents which acknowledged that serious symptoms of agitation could occur after taking the drug for just a few days.

Whistleblower

Dr Healy, now a professor of psychiatry at the North Wales Department of Psychological Medicine, has recently been in the news again, after publishing an article in the scientific literature accusing drug companies and their official regulators of dirty tricks (BMJ, 2006; 333: 92–5).

The target of his concern was the fact that the drugs cause some people to commit suicide: indeed, these highly sophisticated drugs apparently can precipitate the fatal behaviour that psychiatrists spend their lives trying to prevent.

The first warnings of this effect were sounded as early as 1991, when researchers looked at the placebo-controlled clinical evidence for fluoxetine, and discovered a spike of suicides (BMJ, 1991; 303: 685–92).

Drug companies glossed over such findings, and even complained that placebo-controlled trials were unethical, as SSRIs were self-evidently both effective and safe. However, as Professor Healy revealed in his British Medical Journal article, he “obtained access” to some of the original drug-company data, which gave the lie to their official PR line. He was able to confirm that, in the evidence presented to the licensing authorities, “every antidepressant licensed since 1987 [showed] an excess of suicides”.

The companies, he said, had “obscured” the suicide evidence by fudging the data, a practice euphemistically referred to as ‘recoding’.

When Healy challenged Pfizer (which makes sertraline, marketed as Zoloft) and GSK with his bombshell discovery, they didn’t deny that recoding had occurred, but noted that “the FDA [Food and Drug Administration, the US’ ‘watchdog’ regulatory body] has neither criticised these data or the report as inappropriate, nor required additional analyses”.

However, documents obtained under the Freedom of Information Act reveal that FDA regulators were fully aware of the recoding but, says Healy, told the pharma industry that they did not see the SSRI–suicide connection as “a real issue, but rather as a public relations problem”.

And yet, no fewer than four clinical studies published between 1990 and 2000 have shown SSRIs to cause “an increased risk of suicidality”, culminating in a British report entitled ‘Deliberate Self-Harm and Antidepressant Drugs’. This was a survey of the Accident & Emergency case notes from one UK hospital area that revealed a five-and-a-half times extra risk of suicides among people taking SSRIs (Br J Psychiatry, 2000; 177: 551–6).

Slow-acting regulator

Healy showed that there has been collusion between the authorities and the drug companies in putting as good a gloss on the data as possible.

For example, the FDA had a back-door agreement with Pfizer that the sertraline suicide data should be analysed as if it were a constant hazard, even though they knew the evidence clearly shows that suicides peak in the first few weeks of use.

This averaging-out is outright “manipulation of data”, says Healy, because it disguises the true extent of the suicide problem. His own analysis shows that the latest data for paroxetine indicates as much as a fivefold increase in suicide risk, a statistic consistent with previous findings.

Another area of concern is children. Astonishingly, SSRIs have been given to kids as young as two years old, and the figure is rising exponentially for older children, too. For example, sertraline prescriptions for youngsters aged two to 19 tripled in just the 10 years from 1988 to 1998—from 40 million prescriptions to 120 million—after the introduction of fluoxetine (Pediatrics, 2002; 109: 721–7).

Equally surprisingly, very few SSRIs have actually been formally licensed for use by children, so all of this prescribing to them has been ‘off-label’. This term is used to describe when doctors prescribe drugs that have been officially approved for one purpose to treat other, unauthorized conditions.

In fact, few drugs are ever tested

on children. The reasoning behind this practice is that children are simply ‘little adults’, so the hazard profile of a drug may safely be applied to them so long as the appropriate reductions in dosage have been made to accomodate their smaller size.

But this is not necessarily true. For example, Ritalin—the infamous hyper-activity drug—appears to act as a depressant in children, but is a stimulant when taken by adults.
So we know that children can react totally differently from adults, particularly when mood-altering drugs are concerned.

Indeed, in the case of SSRIs, it was largely children’s violently self-harming reactions to the drugs that alerted psychiatrists to the suicide problem in the first place.

In 1991, Yale University doctors reported the case notes of six children, aged 10 to 17, who developed “intense self-injurious ideation or behaviour” while taking Prozac. For example, after three weeks on the drug, one 14-year-old girl, who had never been suicidal before, began cutting and otherwise injuring herself. She told hospital staff, “I’m just waiting for the opportunity to kill myself,” and chanted, “Kill, kill, kill; die, die die; pain, pain, pain” (J Am Acad Child Adolesc Psychiatry, 1991; 30: 179–86).

Another study carried out 10 years later again found that SSRIs increased suicidal behaviour in children (J Am Acad Child Adolesc Psychiatry, 2001; 40: 1364–5).

And yet, it wasn’t until 2003 that the British Medicines and Healthcare Products Regulatory Agency (MHRA) finally recommended that SSRIs not be given to children—and this only after being shamed into action by media reports of teen suicides caused by Seroxat.

Why did they take so long? According to Healy, there were two main reasons: a “lack of statistical expertise” on the part of the MHRA (and the FDA, too); and a mindset which “overstates the benefits and underestimates the risk of drugs”.

As a result, both the British and the American regulatory bodies, he says, insist on such cast-iron statistical proof of harmful effects that they demand “an all but unreachable threshold”.

The crowning irony of this official intransigence came in May of this year, when GlaxoSmithKline themselves sent a letter to doctors, warning them that paroxetine could cause a sixfold increase in the risk of suicides—a figure that neither the FDA nor the MHRA has so far acknowledged.

“Many people expect drug companies to be slow to concede that a drug causes hazards,” commented Healy dryly, “but we do not expect
our regulators to be even slower.”

Major side-effects

Excess suicides are just the beginning. There are also major issues of side-effects and efficacy. After 20 years of experience with SSRIs, it now turns out that these super-sophisticated drugs that were once hoped to be relatively free of side-effects are, in fact, potentially more dangerous than the crude tricyclic antidepressants (TCAs) of the 1950s they were meant to surpass (see box, page 6).

But the SSRI scandal stretches even beyond that. The only reason SSRIs were allowed onto the market in the first place was that the drug companies claimed they were far superior to the existing TCAs. In the heady days of the 1980s, figures of 80 per cent effectiveness were confidently bandied about—this was three times better than with TCAs, said SSRI manufacturers.

But those claims have since turned out to be highly optimistic. Study after study has shown that SSRIs are actually little better than the TCAs. Recently, researchers have pulled together 15 to 20 years’ worth of statistics, including previously sup-pressed data amassed by the drug companies themselves, as a sort of final overall verdict on the SSRI experience.

These huge clinical ‘meta-analyses’ have looked at SSRI use by a variety of patient groups. Here, for example, are direct quotes from what researchers have found in three different types of patients:

• people with mild depression: “. . . no differences between TCAs and SSRIs” (Cochrane Database Syst Rev, 2000; 4: CD001130)
  
• depression in general: “There are no clinically significant differences in effectiveness between SSRIs and TCAs” (Cochrane Database Syst Rev, 2000; 2: CD001851)
  
• The elderly: “. . . SSRIs and TCAs are of the same efficacy” (Cochrane Database Syst Rev, 2006; 1: CD003491).
  

The anger in response to this revelation among the psychiatric profession is now palpable. Even normally conservative medical journals have spoken out against the drugs. An article in a major psychiatric journal recently concluded that drug-company-sponsored research is no longer reliable: “Caution is needed in interpreting drug company sponsored trials given the evidence of selective reporting and publication bias” (Curr Opin Psychiatry, 2005; 18: 21–5).

Similarly, another peer-reviewed journal revealed that, if the true data for these drugs had not been suppressed, it would have served as evidence that they don’t work:

“We learned that pharmaceutical companies selectively released data that reflected positively on their products, and that combining sup-pressed and published data suggested that most of these medications had questionable efficacy” (J Clin Psychol, 2006; 62: 235–41).

Any residual confidence in the SSRIs is now likely to be permanently eroded. However, most of the large pharmaceutical companies that produced the SSRIs will not receive any negative fallout on their share prices. After all, most of the SSRI patents have now expired (see box, page 8). So, it would seem that the drug giants have already made whatever money they can and can now do a runner—a kind of smash-and-grab raid on the world of psychiatry.

Nevertheless, their future share in this lucrative market may be damaged. Pharma-industry analysts warn that “the world antidepressants market is in serious trouble”, with revenues of “only” $7 billion a year—50 per cent down from their peak (The World Market for Antidepressants, 2006).

They also predict that “the world market will crash”, mainly because there are not enough new anti-depressants in the pipeline.

That may indeed be so, but the market may also crash for at least three other reasons, too. The trust that may have existed between psychiatrists and their patients and the pharmaceutical companies is likely to be permanently tarnished. With this whole sorry episode, the biochemical model of depression–and biochemical manipulation as a solution–is now in question. The result is that patients may be more willing to turn to the many safe, natural antidepressants that are available to them.

Tony Edwards