Editors Note: Over the next several months, Mad in America is publishing a serialized version of Peter Gtzsches book, Critical Psychiatry Textbook. In this blog, he describes the way the pharmaceutical industry, and the drug regulators, spun the results of clinical trials to hide suicide attempts and deaths on depression pills. Each Monday, a new section of the book is published, and all chapters are archived here.
Concealing suicide and homicide: fraud, organised crime, and FDAs complicity
Fluoxetine(Prozac or Fontex) was the first SSRI that came into widespread use. The story behind it is a grim one which students of psychiatry should know about, also because this drugs approval paved the way for a host of similar drugs. It illustrates that marketing trumps science totally in influencing if doctors use drugs, and if so, which drugs they use.2,6:202
Fluoxetine is such a terrible drug that senior management in Eli Lillywanted to shelve it after having considered marketing it for eating disorders.2 But Lilly was in serious financial trouble, and if fluoxetine failed, Lilly could go down the tubes.197,343,344
The FDA noted serious flaws in Lillys trials.2 Patients who didnt do well after two weeks had their code broken, and if they were on placebo, they were switched to fluoxeine.345 In this way, six weeks of fluoxetine was compared to two weeks on placebo. It also turned out that 25% of the patients had taken an additional drug, and when the FDA in 1985 removed patients on benzodiazepines and other drugs from Lillys trials, there was no significant effect of fluoxetine.
The FDA went to extremes to make it look like fluoxetine worked.345 Perhaps the fact that Lilly is an American company played a role. Fluoxetine was approved when Bush senior was president and he had been a member of the board of directors of Lilly. Vice President Dan Quayle was from Indiana where Lillys headquarters are, and he had former Lilly personnel on his own staff and sat on an FDA oversight committee.21
The German drug regulator considered fluoxetine totally unsuitable for the treatment of depression and furthermore noted that, according to the patients self-ratings, there was little or no response, in contrast to doctors ratings.2,5,346 This is also the case for other depression pills, and also for children. When the patients evaluate the effect themselves, it is non-existent (effect size 0.05 or 0.06).347,348,349 Only the psychiatrists think they work (effect sizes 0.25 to 0.29) but they are not the ones to be treated.
When Lilly showed some of its data to Swedish psychiatrists, they laughed and didnt think Lilly was serious.350 But it was crucial to get fluoxetine approved in Sweden, as it would then be easier to get it approved by the FDA. Lillys Swedish director, John Virapen, invited doctors to the Caribbean for a week, with plenty of relaxation, including diving, surfing, sailing, pretty girls and hot nights.350 He came to Copenhagen to visit me to tell me more about this than he published in his book,350 and official documents confirm his story.7:59
By planting indirect questions to the secretaries of prominent psychiatrists, Virapen identified the independent expert, psychiatrist Anders Forsman, who was going to examine the clinical documentation for the Swedish drug agency. Forsman was one of those who had laughed about the idea of ever getting fluoxetine approved, but already at their second meeting, he suggested $20,000 as a reasonable sum for a speedy approval, which, moreover, shouldnt become known to the taxman but was to be handled by Lillys office in Genve. He furthermore demanded a good deal of research money. The money was split and the second half was to be paid when the drug was approved. This is how the mob operates when it orders a murder.
Forsman even suggested falsifying the registration application, e.g. suicide attempts were called miscellaneous effects, and he placed his own personal letter of recommendation.
As the criteria for the depression diagnosis were much more stringent and relevant than today, there werent many depressed people at the time, and fluoxetine was therefore marketed as a mood lifter, like street pushers sell cocaine.
The approval in Germany also followed unorthodox lobbying methods exercised on independent members of the regulatory authorities, as Virapen called it.350 After having been so enormously helpful to Lilly, Virapen was fired. This is also like in the mob. When a lower-ranked person has been asked to murder a well-known political figure, it is safest to kill the assassin afterwards. The official explanation was that Lilly had certain ethical principles. When journalists ask me what I think of the ethical principles of the drug industry, I say I have no answer as I cannot describe what doesnt exist. The only industry principle is money, and the worse the crime, the more money will be earned.6
Forsmans name became known in the press, but he just went on and came to work for the court, as a psychiatric assessor for Sweden. Virapen tried to prosecute him, but that wasnt possible because he wasnt an employee of the health authority. After this affair, the Swedish anti-corruption law was amended.
Lilly turned their awful drug, which they didnt even like themselves, into a blockbuster, which contributed to making the company one of the worlds ten biggest.
Lilly promoted fluoxetine illegally for several non-approved ailments, e.g. shyness, eating disorders, and low self-esteem, and concealed that the drug causes suicide and violence.2,122,351
In 1990, only two years after fluoxetine came on the market, Martin Teicheret al. described six patients who had become suicidal and reacted in bizarre ways with intense, violent suicidal preoccupation while receiving the drug, which was something completely new to them.352 Teichers observations were very convincing. Later, however, internal Lilly documents that came to light during a litigation case353 revealed that the FDA worked with Lilly on the suicide issue. The psychiatrists Lilly had corrupted came in handy while Lillys own scientist left out information at the subsequent 1991 FDA hearings that demonstrated that fluoxetine increases the risk of suicide.122 Earlier, Lilly had submitted data to the German drug agency showing that suicide attempts almost doubled on fluoxetine compared to placebo.
The chair of the FDA committee, psychiatrist Daniel Casey, brutally interrupted Teicher so that he couldnt present his findings and reasons. He was only allowed to present a few slides while Lilly staff presented many. A few years later, Teichers wife was offered a job at Lilly as their top scientist in oncology without having applied, which she accepted.
in 2004, the BMJ received a series of internal Lilly documents and studies on fluoxetine from an anonymous source, which had been available ten years earlier in a litigation case.353 They revealed that Lilly had known since 1978ten years before fluoxetine came on the marketthat fluoxetine can produce in some people a strange, agitated state of mind that can trigger in them an unstoppable urge to commit suicide or murder.344 In 1985, two years before fluoxetine was approved, the FDAs safety reviewer noted under the headline Catastrophic and serious events that some psychotic episodes had not been reported by Lilly but were detected by the FDA by examining case reports on microfiche. The reviewer noted that fluoxetines profile of adverse effects resembled that of a stimulant drug, which might be the reason why Lilly marketed fluoxetine as a mood lifter.
Already in 1985, an in-house analysis of placebo-controlled trials found 12 suicide attempts on fluoxetine versus one on placebo, but after the code was broken, Lillys hired consultants threw out six of the attempts on fluoxetine.111:258
Lilly was keen to root out the word suicide altogether from its database of adverse events experienced by patients and suggested that, when doctors reported a suicide attempt on fluoxetine, Lilly staff should code it as overdose.
Lillys fraud was second to none. It is hardly possible to kill yourself by overdosing fluoxetine, and the suicides occur on normal doses. Furthermore, Lilly excluded 76 of 97 cases of suicidality on fluoxetine in a post-marketing surveillance study it submitted to the FDA.354,355 Lilly instructed its staff to code suicidal ideation as depression,197 which is the usual script for drug companies, drug regulators, and psychiatrists: Blame the disease, not the drug.7:208
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.354 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 taken duloxetine, another Lilly drug. When a BMJ journalist, Jeanne Lenzer, filed Freedom of Information Act requests for all safety data related to duloxetine she received a database that included 41 deaths and 13 suicides. Missing from the database was any record of the college student and at least four other volunteers known to have committed suicide while taking duloxetine for depression.354
One of the leaked documents noted that in clinical trials, 38% of fluoxetine-treated patients reported new activation compared to only 19% of placebo-treated patients. Activation may lead to agitation or akathisia, and Lilly recommended early on that, in their trials of fluoxetine, such patients should also take benzodiazepines,2 which reduce the symptoms. We therefore dont know what the true extent of akathisia is. Other companies adopted the same strategy, and minor tranquillisers were permitted in 84% of placebo-controlled trials of depression pills.356
Lillys widespread criminal activities and corruption of doctors worked. In 1997, Prozac was the fifth most prescribed drug in the United States.357 It also became the most complained-about drug.1:287
In relation to lawsuits, Healy found early drafts of Prozacs package insert that stated that psychosis might be precipitated in susceptible patients by depression pills.357 The warning about psychosis wasnt included in the final package insert for the United States, and is not even included today,33 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.2:171 As always, the FDA protected the drug and not the patients, as it said it would not have allowed a company to put a warning about akathisia or suicide on the label; it would have considered it mislabelling.357
Other companies also indulged in fraud and organised crime.6:208 SmithKline Beecham, later merged into GSK, started marketing paroxetine(Paxil or Seroxat) in 1992 and falsely claimed for the next 10 years that it wasnt habit forming358 even though the licence application showed that paroxetine leads to withdrawal reactions in 30% of the patients.359 The UK drug regulator also denied there was a problem whereas the BBC reported in 2001 that WHO had found Paxil to have the hardest withdrawal problems of any depression pill. Until 2003, the UK drug regulator propagated the falsehood that SSRIs are not addictive, but the same year, WHO published a report that noted that three SSRIs (fluoxetine, paroxetine and sertraline) were among the top 30 highest-ranking drugs for which drug dependence had ever been reported.307
The UK drug regulator also misrepresented the data when it described withdrawal reactions as generally being rare and mild. Independent researchers showed that the reactions had been classified as moderate in 60% of the cases and as severe in 20% by the same UK regulator that told the public that they were mild.360
In 2003, GSK quietly and in small print revised its previous estimate of the risk of withdrawal reactionsin the prescribing instructions from 0.2% to 25%,307 a 100-times increase.
From 2002 onwards, the BBC presented four documentaries about SSRIs in its Panorama series, the first one called Secrets of Seroxat. The GSK spokesperson, doctor Alastair Benbow, lied in front of a running camera. He denied that paroxetine could cause suicidality or self-harm, while he sent data to the drug regulator one month later that showed exactly this, and which immediately led to a ban on using the drug in children.
The drug regulator claimed that this information was completely new to GSK, which, however, had known about it for ten years. In addition, the head of the drug agency echoed the drug companies false assertion that it was the disease, not the drug, that caused the suicidal events.
US senator Charles Grassleyasked GSK for how long the company had known that paroxetine carried a suicide risk.361 GSK lied when it wrote back that they detected no signal of any possible association between Paxil and suicidality in adult patients until late February 2006. Government investigators found that the company had the data in 1998 and Healy found evidence in internal company documents that 25% of healthy volunteersexperienced agitation and other symptoms of akathisia while taking paroxetine.357
Healyperformed a study of sertraline in 20 healthy volunteers, and to his big surprise two of them became suicidal.2:179 One was on her way out the door to kill herself in front of a train or a car when a phone call saved her. Both volunteers remained disturbed several months later and seriously questioned the stability of their personalities.
Pfizers own studies in healthy volunteers showed similar deleterious effects, but they hid most of the data in company files.
Drug regulators also hid the lethal harms. When FDA reviewers and independent researchers had found that the drug companies had concealed cases of suicidal thoughts and acts by labelling them emotional lability, the FDAbosses suppressed this information.2,362 When the FDAs own safety officer, Andrew Mosholder,concluded that SSRIs increase the suicide risk among teenagers, the FDA prevented him from presenting his findings at an advisory meeting and suppressed his report. When the report was leaked, the FDAs reaction was to do a criminal investigation into the leak.355,363
There were other types of fraud. In data submitted by GSK to the FDA in the late 1980s and early 1990s, the company had added suicide attempts from the washout period before the patients were randomised to the results for the placebo group, but not to those for the paroxetine group. At least three companies, GSK, Lilly, and Pfizer, added cases of suicide and suicide attempts in patients to the placebo arm of their trials, although they didnt occur while the patients were randomised to placebo.2,141,353,364,365
Healy wrote in 2002364 that, based on data he had obtained from the FDA, three of five suicide attempts on placebo in a sertraline trial366 had occurred during washout rather than on placebo and that two suicides and three of six attempts on placebo in a paroxetine trial366 had also occurred in the washout period. Healys observations werent denied by Pfizer and GSK,367,368 but GSKprovided another glaring example that their lies are not of this world:368
The drug v. true placebo analysis Dr Healy describes is not only scientifically invalid, but also misleading. Major depressive disorder is a potentially very serious illness associated with substantial morbidity, mortality, suicidal ideation, suicide attempts and completed suicide. Unwarranted conclusions about the use and risk of antidepressants, including paroxetine, do a disservice to patients and physicians.
The systematic fraudcan be important for the companies in court cases. In 2001, when a man on paroxetine had murdered his wife, daughter, and granddaughter and committed suicide, GSK said in its defence that its trials didnt show an increased risk of suicide on paroxetine.369 This seemed to be incorrect. In 2004, a researcher published a meta-analysis based on the full reports of GSKs trials that were made available on the Internet as a result of litigation. He found that paroxetine increased significantly suicidal tendencies, odds ratio 2.77 (1.03 to 7.41).370
The clinical study reports we analysed also included trials in adults.326 We could not address the harms fully because some of them appeared only in patient listings in appendices, which we had for only 32 of our 70 included trials. Furthermore, we didnt have case report forms. But we found many alarming events, which you will never see in medical journals and here are some:
Four deaths were misreported by the company, in all cases favouring the active drug.
A patient receiving venlafaxine attempted suicide by strangulation without forewarning and died five days later in hospital. Although the suicide attempt occurred on day 21 out of the 56 days of randomised treatment, the death was called a post-study event as it occurred in hospital and the drug had been discontinued because of the suicide attempt.
Although patient narratives or individual patient listings showed they were suicide attempts, 27 of 62 such attempts were coded as emotional lability or worsening depression, which is what you see in the publications, not the suicide attempts.
A suicide attempt (intentional overdose with paracetamol in a patient on fluoxetine) was described in the adverse events tables as elevated liver enzymes, which you can get if you drink alcohol.
For Eli Lillysdrugs, fluoxetine and duloxetine, we compared our findings with the summary trial reports on the companys website. Lillys reporting was seriously misleading.8,326 In most cases, adverse events were only shown if they occurred in, for example, at least 5% of the patients. In this way, the companies may avoid reporting many serious harms. Only 2 of 20 suicide attempts (17 on drug, 3 on placebo) were documented. None of 14 suicidal ideation events (11 vs 3) were mentioned, and only 3 akathisia events (15 vs 2) were mentioned.
In three sertraline trials where we had access to both the verbatim and the coded preferred terms, akathisia was coded as hyperkinesia, and miscoding seemed to have been prevalent also in paroxetine trials since we didnt find a single case of akathisia.
As explained earlier, akathisia increases the risk of suicide, violence, and homicide. We could only identify akathisiaif we had access to the verbatim terms, but we nonetheless found that, like aggression, akathisia was seen twice as often on the pills than on placebo.326
It is of particular relevance for the many school shootingsthat the following events for 11 patients on a depression pill were listed under aggression in patient narratives for serious adverse events: homicidal threat, homicidal ideation, assault, sexual molestation, a threat to take a gun to school, damage to property, punching household items, aggressive assault, verbally abusive and aggressive threats, and belligerence.
Many of the killers were on depression pills. The authorities routinely hide such information in order not to raise concerns about the safety of the pills, and it therefore took quite a while before we learned that the Germanwings pilot that took a whole plane with him when he committed suicide in the Alps, and that the Belgian bus driver who killed many children by driving his bus into a wall, also in the Alps, were both on a depression pill.
To see the list of all references cited,click here.
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