The first SSRI was fluoxetine (Prozac), which was marketed in 1988. It’s a terrible drug and senior management in Lilly wanted to shelve it.24 But Lilly had a problem. It was in serious financial trouble, and if Prozac failed, Lilly could ‘go down the tubes’.66,67,68
Fluoxetine is such a poor drug that the German drug regulator concluded in its assessment: ‘Considering the benefit and the risk, we think this preparation totally unsuitable for the treatment of depression.’24,69 When Eli Lilly showed some of its data to Swedish psychiatrists, they laughed and didn’t think Lilly was serious about seeking approval for the drug,70 and the FDA noted serious flaws in the trials.24
However, to survive as a company, Lilly was determined to make Prozac a success, and it was crucial to get Prozac approved in Sweden, as it would then be easier to get it approved by the FDA. The vice president for Europe left no doubt that the managing director for Sweden, John Virapen, needed to do whatever it took to succeed.
Virapen, who felt his future career at Lilly depended on approval of Prozac, solved his problem with bribery. He launched seeding trials before the drug was approved and invited doctors to the Caribbean for a week, with plenty of relaxation, including ‘diving, surfing, sailing, pretty girls and hot nights’.70 By planting indirect questions to the secretaries of prominent psychiatrists, Virapen found out the identity of the independent expert who was going to examine the clinical documentation for the Swedish drug agency. The expert didn’t like fluoxetine at all and just 2 weeks earlier, he had laughed about the idea of ever getting fluoxetine approved. However, already at their second meeting, he suggested $20 000 as a reasonable sum for a speedy approval, which, moreover, shouldn’t become known to the taxman but was to be handled by Lilly’s office in Geneva. He furthermore demanded that Lilly provided a good deal of research money to his department. The money was split so that the second half was to be paid when the drug was approved. This is how the mob operates when it orders a murder.
Next, one of Virapen’s associates met with the expert in Göteborg to improve on the registration application. Deaths disappeared in footnotes and it went somewhat like this:
‘Five had hallucinations and tried to commit suicide, which four of the test subjects succeeded in doing’ was changed into: ‘Five of the other test subjects had miscellaneous effects.’
On top of this, the independent expert placed his own personal letter of recommendation. It didn’t take long before Virapen received a phone call to start negotiations about what the drug should cost, which meant the drug would be approved. When the price had been settled for a 20 mg dose, a top psychiatrist who had done research with fluoxetine postponed approval as she found that 5 mg was the maximum that should be allowed, and she demanded that the 5 mg dose should be made available. However, Lilly managed to avoid this, which might potentially have reduced its income by 75%.
There weren’t that many truly depressed people in the mid-1980s when the criteria for the diagnosis were much more stringent and relevant than today, and fluoxetine was therefore marketed as a mood lifter. Isn’t that something? A drug with cocaine-like effects is marketed as a mood lifter! What’s the difference to street pushers?
The approval in Germany also followed ‘unorthodox lobbying methods exercised on independent members of the regulatory authorities’.70
After having been so enormously helpful to Lilly, Virapen was fired. This is also like a script from the mob. When the boss has persuaded a lower-ranked person to murder a well-known political figure, it is safest to kill the assassin soon afterwards, as a dead man doesn’t talk. The official explanation was that Lilly had certain ethical principles! Two other people who knew about the bribery were also fired without reason. Virapen tried to persecute the corrupt psychiatrist, but that wasn’t possible because the psychiatrist wasn’t an employee of the health authority. After this affair, the Swedish anticorruption law was amended. The psychiatrist just went on and, ironically, came to work for the court, as a psychiatric assessor for Sweden.
Eli Lilly promoted Prozac illegally for several non-approved ailments, e.g. shyness, eating disorders and low self-esteem, and concealed the increased risk of suicide and violence associated with the drug.1,24,71 However, in 1990, only 2 years after Prozac came on the market, Martin Teicher et al. described six patients who had become suicidal and reacted in bizarre ways with intense, violent suicidal preoccupation while receiving Prozac, which was something completely new to them.72 Teicher’s observations were ground-breaking and the paper was highly convincing. However, internal Lilly documents revealed later that the FDA worked together with the company on the suicide issue, and Lilly’s hired guns among the psychiatrists came in handy while Lilly’s own scientist left out information that would have been incriminating for the company at the subsequent 1991 FDA hearings.1 The chair of the FDA committee, psychiatrist Daniel Casey, brutally interrupted Teicher so that he couldn’t present his findings and reasons! He was only allowed to present a few slides while Lilly staff presented many. A few years later, Teicher’s wife was offered a job at Lilly as their top scientist in oncology without having applied. This was hardly a coincidence. The standard procedure is to blacklist and haunt critical people and if that doesn’t work, to buy them or their close relatives. His wife divorced Teicher and went to work for Lilly.
In 2004, the BMJ received a series of internal Lilly documents and studies on Prozac from an anonymous source, which the journal sent to the FDA.73 These documents were made available in a litigation case in 1994, but were not accessible for the public. They revealed that Lilly officials were aware already in the 1980s that fluoxetine had troubling side effects in terms of suicide attempts and violence and sought to minimise their negative effect on prescribing. Lilly was keen to root out the word ‘suicide’ altogether from its database record of side effects experienced by patients and its headquarters suggested that, when doctors reported a suicide attempt on Prozac to Lilly, it should be coded as ‘overdose’ (which is terribly misleading, as it is hardly possible to kill yourself by overdosing Prozac; the suicides occur on normal doses), and ‘suicidal ideation’ should be recorded as ‘depression’ (blame the disease, not the drug).68 Two Lilly researchers in Germany were unhappy with these directions: ‘I do not think I could explain to the BGA [the German regulator], 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.’24,74
One of the documents the BMJ received noted that in clinical trials, 38% of fluoxetine-treated patients reported new activation compared to only 19% of placebo-treated patients. SSRIs often lead to agitation or akathisia, an extreme form of restlessness, which some patients describe as wanting to jump out of their skin, and which increases the risk of suicide.1,24 Early on, Lilly recommended that in their trials of fluoxetine such patients should also take benzodiazepines,24 which reduce the symptoms. We therefore don’t know what the true side effects are, or even what the true effect on depression is, as benzodiazepines have an effect on depression.
However, when Lilly became interested in showing that its drug, Prozac, led to fewer withdrawal symptoms than its competitors’ drugs because of its longer half-life, the result was overwhelming. More than half of the patients on paroxetine and sertraline developed abstinence symptoms within a week when they were switched from active drug to placebo.62,75 The most frequent symptoms clearly had nothing to do with relapse of the depression but with abstinence: worsened mood, irritability and agitation.
The bias in industry-sponsored trials is really massive. In head-to-head trials where Prozac was the drug of interest, significantly more patients improved on Prozac than in trials where Prozac was the comparator drug.76
In 2004, the FDA issued a warning that antidepressants can cause a cluster of activating or stimulating symptoms such as agitation, panic attacks, insomnia and aggressiveness. Such effects were expected, as fluoxetine is similar to cocaine in its effects on serotonin.73 Inter
estingly, however, when the EMA in 2000 continued to deny that the use of SSRIs leads to dependence, it nonetheless stated that SSRIs ‘have been shown to reduce intake of addictive substances like cocaine and ethanol. The interpretation of this aspect is difficult.’77 The interpretation is only difficult for those who are so blind that they will not see.
In 1989, a man shot eight people dead, wounded another 12 and then killed himself 1 month after he was placed on fluoxetine.73 Lilly won a nine to three jury verdict and subsequently claimed it was ‘proven in a court of law … that Prozac is safe and effective’. However, the trial judge, who suspected that a secret deal had been struck, pursued Lilly and the plaintiffs, eventually forcing Lilly to admit that it had made a secret settlement with the plaintiffs during the trial. Infuriated by Lilly’s actions, the judge ordered the finding changed from a verdict in Lilly’s favour to one of ‘dismissed as settled with prejudice’, saying, ‘Lilly sought to buy not just the verdict but the court’s judgment as well.’
Lilly also bought FDA panel members. An FDA advisory panel was convened in 1991 to review the fluoxetine data. It concluded that fluoxetine was safe despite the concerns raised by safety officer David Graham and others, which led critics to point out that several of the panellists had financial ties to Lilly.
Throughout the 1990s, while swearing publicly that Prozac didn’t increase the risk of suicide or violence, Lilly quietly settled lawsuits out of court and was able to keep the incriminating evidence hidden by obtaining court orders to seal the documents, just as it had done with its best-selling antipsychotic drug, Zyprexa (olanzapine), until a batch of documents was leaked to the press.71
Lilly’s internal papers disclose a long and successful battle against the idea that Prozac could induce violence or suicide, and they suggest that Lilly had an explicit strategy to blame the disease and not the drug, which some of Lilly’s own scientists had reservations about. Some of Lilly’s actions appeared fraudulent, e.g. the company excluded 76 of 97 cases of suicidality on Prozac in a post-marketing surveillance study it submitted to the FDA.78,79
In 1997, Prozac was the fifth most prescribed drug in the United States.80 It also became the most complained-about drug, and hundreds of suicides were reported.21 In relation to lawsuits, David Healy found early drafts of Prozac’s package insert that stated that psychosis might be precipitated in susceptible patients by antidepressant therapy.80 It turned out that Lilly had known since 1978 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.67 The warning about induction of psychosis wasn’t included in the final package insert for the United States, whereas the German drug agency required it. By 1999, the FDA had received reports of over 2000 Prozac-associated suicides and a quarter of the reports specifically referred to agitation and akathisia. As always, the FDA protected the drug and not the patients, as it said that it would not have allowed a company to put a warning about akathisia or suicide on the label; it would have considered it mislabelling!80 The EMA announced in 2006 that parents and doctors should carefully monitor children and youth being treated with fluoxetine and watch out for suicidal tendencies.70 A fake fix. Children commit suicide whatever the warnings are. Fluoxetine should never have been approved for children, or indeed for any creature, not even dogs (SSRIs are used for ‘separation anxiety’ in dogs, which is when dogs howl too much when their owner leaves home).
Lilly also kept completed suicides from public view. In 2004, the body of a 19-year-old college student was found hanging by a scarf from a shower rod in an Indianapolis laboratory run by Lilly.78 She had entered a clinical study as a healthy volunteer in order to help pay her college tuition after having undergone thorough medical testing to screen out depression or suicidal tendencies. She had not taken Prozac but another SSRI, duloxetine (Cymbalta), which Lilly wanted to develop for stress urinary incontinence under the trade name Yentreve. When researchers and the press started asking questions about duloxetine, the FDA didn’t scour its database and go public. It kept quiet and gave a legal rationale for its silence:
Some clinical trial data are considered trade secrets, or commercially protected information.
It is outrageous that a drug regulator puts profits over human lives in this way. Clinical trial data are not trade secrets (see Chapter 11), and the FDA must change its attitudes and bring them on par with those at the EMA. A BMJ journalist, Jeanne Lenzer, filed several Freedom of Information Act requests for all safety data related to Cymbalta and Yentreve and received a database that included 41 deaths and 13 suicides among patients taking Cymbalta. Missing from the database was any record of the college student and at least four other volunteers known to have committed suicide while taking Cymbalta for depression.
Lilly admitted that it had never made public at least two of those deaths, and anonymous sources told Lenzer that duloxetine caused suicidal tendencies in patients who took the drug for incontinence and who weren’t depressed. Lenzer couldn’t get access to these data, as the FDA is prohibited from releasing study data for a drug that fails to win FDA approval, and the FDA didn’t approve Yentreve. It cannot be more absurd than this, as the active chemical is the same in Yentreve as in Cymbalta. The United States must change their laws so that they serve the public.
The FDA did state later, however, that data from stress urinary incontinence trials had shown that middle-aged women taking duloxetine had a suicide attempt rate of 400 per 100 000 person-years, more than double the rate of about 160 per 100 000 person-years among other women of a similar age. This suggests that SSRIs are not only dangerous in children but also in adults (see Chapter 18).
There is one more take-home message from this sad affair. Volunteers, like the dead college student, are told that even if they don’t personally benefit from taking a new drug, the scientific knowledge gained from the study will benefit others. The volunteers should be told instead that people will learn about their experience only if it’s good news for the company. It’s unbelievable and deeply criminal that healthy volunteers can die without anyone knowing about it outside the company.
When Lenzer asked Lilly about Prozac again because the sealed internal Lilly documents had surfaced, Lilly sent her a written statement:73 ‘Prozac has helped to significantly improve millions of lives. It is one of the most studied drugs in the history of medicine, and has been prescribed for more than 50 million people worldwide.’
When drug companies face trouble, they always try to escape by using big numbers. Millions of lives have not been improved significantly. In randomised trials, equally many patients stop treatment while on an SSRI as while on placebo, which suggests that, overall, considering benefits and harms together, the drugs are pretty useless.81 A 2003–2007 study of 7525 patients starting antidepressants, of which two-thirds were SSRIs, showed that already after 2 months, half of the patients had stopped taking the drug.82 What 50 million people tell us is that millions of people have been harmed, as many of those who continue to take the drug become addicted and cannot stop.
Exercise is a good intervention
It’s not an exaggeration to say that antidepressant research is under total industry control; it supplies randomised pseudo-evidence for multibillion-dollar markets.83 When we say that 50% improve on placebo and 60% on active drug,84 it looks better than it really is (see Chapter 4). The improvement on the most used scale, Hamilton’s depression scale, is so small that the drugs only seem to give a meaningful effect in patients who are rather severely depressed, which is a tiny fraction of all those treated in clinical practice.85,86 Further, it has never been shown in trials or high-quality observational studies that the use of antidepressant drugs lowers suicide rates. Contrast these facts with a 2013 statement from the president of the American Psychiatric Association, Jeffrey Lieberman:87
‘As a class, antidepressant medications are highly effective. They alleviate substantial amounts, if not complete symptoms, in 50 to as
high as 80% of patients treated who suffer from major depression.’
Any higher bets? With such a monstrous exaggeration, why not go all the way and say the drugs cure 100%?
It would be far better to encourage people to exercise than to take drugs. There are few long-term comparisons between SSRIs and exercise, but those that exist are interesting. In a 4-month trial of 156 patients with major depression, the effect was similar for those randomised to exercise as for those who received sertraline (Zoloft), but 6 months later, only 30% of the patients in the exercise group were depressed, as compared with 52% in the sertraline group and 55% in a group that was randomised to both exercise and sertraline.88 These differences were seen despite a low treatment contrast: 64% of patients in the exercise group and 66% in the combination group reported that they continued to exercise, but 48% of the sertraline patients also initiated an exercise programme. A Cochrane review of exercise found an effect on depression that was very similar to that reported for SSRIs.89
A 24-week randomised trial of 375 patients with social phobia found a similar effect of gradual exposure to the feared symptoms as of sertraline, but during an additional 6-month follow-up, the exposure group continued to improve whereas the patients from the sertraline group did not.90 Social phobia was a rare disease until the drug companies hijacked it and called it social anxiety disorder. They boosted sales tremendously, aided by PR firms and their whores among psychiatrists and patient organisations.9 The pool of patients went up from about 2% to 13% – or one in every eight people – handsomely helped by the ludicrous criteria in DSM that broadened over time.
Further lies about happy pills
SmithKline Beecham, later merged into GlaxoSmithKline, started marketing paroxetine (Paxil or Seroxat) in 1992 and falsely claimed for the next 10 years that it wasn’t habit forming.91 That was pretty misleading considering that, in the original licence application, paroxetine led to withdrawal reactions in 30% of the patients!92 The UK drug regulator also denied there was a problem and failed to warn of the lack of evidence of SSRI effectiveness in mild depression. In 2001, the BBC reported that the World Health Organization had found Paxil to have the hardest withdrawal problems of any antidepressant drug. In 2002, the FDA published a warning, and the International Federation of Pharmaceutical Manufacturers Associations declared the company guilty of misleading the public about paroxetine on US television. In 2003, Glaxo quietly and in small print revised its previous estimate of the risk of withdrawal reactions in the prescribing instructions from 0.2% to 25%,62 a 100 times increase.
Deadly Medicines and Organised Crime Page 36