I had a big laugh when I saw the four references in support of these statements. Paper is grateful, as we say; it doesn’t protest, no matter what you write on it. One of the academic authors was Stuart Montgomery, who concealed that he worked for Pfizer helping the company to get sertraline approved at the same time as he worked for the UK drug regulator that approved the drug (see Chapter 10). I laughed again when an employee from the institute was interviewed in the TV news. She was pressured by the journalist who asked her if she couldn’t imagine any situation where it might be an advantage that the drug worked faster. Yes, she said, if a patient was about to throw herself out the window! She learned the hard way how to deal with journalists. Jokes won’t do on the news, particularly not if they are about patients. It was doubly ironic, as it has never been demonstrated that SSRIs decrease the risk of suicide; they seem to increase the risk (see above).
Four independent reviews of the evidence – by the FDA, the American advisory group Micromedex, the Stockholm Medical Council and the Danish institute – concluded that escitalopram offers no significant benefit over its predecessor.47 The Cochrane review on escitalopram says that it’s better than citalopram but warns against this finding because of potential sponsorship bias.48 The trials were performed by Lundbeck and many negative antidepressant trials never get published. Furthermore, the reporting of the outcomes in the included studies was often unclear or incomplete. Analyses made by disinterested parties who have access to the data, such as scientists working at drug agencies, have repeatedly found that there are no important differences in benefits and harms of the various SSRIs, whereas what gets published is seriously misleading.29,42,49 Comprehensive reviews by other researchers have also failed to find important differences.50
In 2003, Lundbeck breached the UK industry code of practice in its advertising.51 The company breached the code on five counts, notably by claiming that ‘Cipralex is significantly more effective than Cipramil in treating depression’. The company also attributed adverse effects to citalopram in its literature on escitalopram that weren’t mentioned in promotional material for citalopram. This confirms the adage that it’s surprising how quickly a good drug becomes a bad drug when a more expensive drug comes around. The UK advertising campaign was intensive and highly successful, as escitalopram rapidly gained market share.
Lundbeck’s CEO, Erik Sprunk-Jansen, retired in 2003 and started a company selling herbal medicine. One of the products is Masculine, which ‘Spices up your love life’, and is said to give extra energy that strengthens the lust and blood circulation,52 typical mumbo-jumbo pep talk for alternative medicine. It doesn’t seem to matter much what drug pushers sell, as long as they sell something.
In 2011, we asked Lundbeck for unpublished trials of its antidepressant drugs, which we needed for our research on suicidality, but we were told that the company, as a matter of principle, doesn’t hand out the clinical documentation that forms the basis for marketing authorisation. The same year, Lundbeck’s new CEO, Ulf Wiinberg, denied in an interview that the increase in suicidal events with happy pills in children and adolescents means that the drugs increase the risk of suicide.53 He even stated that treatment of depression in children and adolescents decreases the suicide risk, in violation of the labelling that warns that the drugs may increase the risk of suicide. Why does any doctor trust what the companies tell them?
Events in America were also interesting. In 2001, Lundbeck’s American partner Forest had performed a trial of citalopram (Celexa) for compulsive shopping disorder (I’m not joking), and Good Morning America told the viewers that this new disorder could affect as many as 20 million Americans of which 90% were women.54 Gorman appeared as an expert in the programme and said that 80% of the compulsive shoppers had slowed their purchases on Celexa. The ensuing flurry of publicity forced the APA to say it had no intention of adding such a disorder to the DSM.
In 2010, the US Justice Department announced that Forest had pleaded guilty to charges relating to obstruction of justice and the illegal promotion of citalopram (Celexa) and escitalopram (Lexapro) for use in treating children and adolescents with depression.55 Forest agreed to pay more than $313 million to resolve criminal and civil liability arising from these matters and also faced numerous court cases from parents to children who had either committed suicide or had tried.56 There were also charges that the company launched seeding studies, which were marketing efforts to promote the drugs’ use. Two whistle-blowers would receive approximately $14 million, and Forest signed a Corporate Integrity Agreement.55,57 Six years earlier, a Forest executive had testified before Congress that Forest followed the law and had not promoted Celexa and Lexapro to children, although Forest had illegally done exactly that.58
The government mentioned that Forest publicised and circulated the positive results of a double-blind, placebo-controlled Forest study in 2004 on the use of Celexa in adolescents while, at the same time, failed to discuss the negative results of a contemporaneous double-blind, placebo-controlled Lundbeck study on the use of Celexa in adolescents, finished in 2002 in Europe but only mentioned in a textbook in Danish in 2003 in a single line of a chart.59 For 3 years, Forest executives didn’t disclose those results within the company or to outside researchers who published results on Celexa, and the existence of the Lundbeck study first came to public light when the New York Times published an article about it. Only then did Forest acknowledge the study as well as another, earlier trial that also failed to show any benefits of Lexapro as a depression treatment for children.55,57
Forest’s official excuse for not mentioning the negative trials was that ‘there was no citable public reference for the authors to examine’.59 But drug makers often announce trials with positive results without waiting for the results to be published, e.g. Forest issued a news release that highlighted the outcome of the positive Celexa trial already in 2001, shortly after the trial’s completion.
Forest had 19 000 advisory board members58 and used illegal kickbacks to induce physicians and others to prescribe Celexa and Lexapro, which allegedly included cash payments disguised as grants or consulting fees, expensive meals and lavish entertainment. On one occasion, Forest paid physicians five hundred dollars to dine at one of the most expensive restaurants in Manhattan and called them consultants – for the evening it seemed, and they didn’t do any consulting.54 Vermont officials found that Forest’s payments to doctors in 2008 were surpassed only by those of Eli Lilly, Pfizer, Novartis and Merck – companies with annual sales that were five to 10 times larger than Forest’s.60
What was Lundbeck’s reaction to the crimes? ‘We know Forest is a decent and ethically responsible firm and we are therefore certain that this is an isolated error.’56 Perhaps this confidence in Forest’s business ethics was related to the fact that Lexapro sold for $2.3 billion in 2008.57 At any rate, we do know something about what it means to be ‘a decent and ethically responsible firm’. In 2009, the US Senate released documents it had requested from Forest.61 They start out by saying that Forest will communicate that Lexapro offers superior efficacy and tolerability over all SSRIs, which is pure fantasy.
We are also told that the antidepressant market is the most heavily detailed category in the drug industry and that the sales mirror the promotional effort. Forest will develop ghostwritten articles for ‘thought leaders’, which will ‘allow us to fold Lexapro messages’, and will also use thought leaders at sponsored symposia, which will be published in supplements to medical journals to ‘help disseminate relevant Lexapro data and messages to key target audiences’.
The thought leaders, advisors and Lexapro investigators will be kept informed by monthly mailings, and Forest will use the consultant services of thought leaders and advisors to obtain critical feedback and recommendations on ‘educational and promotional strategies and tactics’. Forest recruited about 2000 psychiatrists and primary care physicians whom the company trained to ‘serve as faculty for the Lexapro Speakers’ Bureau Program’
. It was obligatory that speakers used the slide kit prepared by Forest.
The documents include details of a huge programme of phase IV studies (seeding trials it seems) and describe that investigator grants would cover the costs of ‘Thought Leader Initiated Phase IV studies with Lexapro’. The outcome of all these studies seemed to have been determined beforehand, even before the studies started, as key messages were listed for each study:
Escitalopram has the lowest potential for drug interactions
Escitalopram has an excellent dosing profile
Escitalopram represents a new more selective and/or potent generation of SSRIs
Escitalopram is an effective first-line treatment for depression
Escitalopram has a favourable side-effect profile
Escitalopram has improved side-effect, drug interaction and safety profiles resulting from the removal of the inactive moiety, the R-enantiomer
Escitalopram is a refinement of citalopram in terms of antidepressant effect and tolerability.
Forest provided ‘unrestricted grants’ to professional societies, e.g. the American Psychiatric Association, so that they could develop ‘reasonable practice’ guidelines. What was meant by this was ‘to improve the percent of patients who adhere to the full duration of therapy’. Forest became a corporate sponsor of the American College of Physicians ‘which provides additional marketing opportunities’, and this organisation was also involved with developing the ‘reasonable practice’ guidelines.
I could throw up. Total corruption of academic medicine resulting in immense harms to patients who cannot get off the drug once they have adhered to ‘the full duration of therapy’. So this is a ‘decent and ethically responsible firm’,56 right?
Antipsychotic drugs
Antipsychotics are dangerous drugs that should only be used if there is a compelling reason, and preferably as short-term therapy at a low dose because the drugs produce severe and permanent brain damage. As explained above, even most patients with schizophrenia can avoid the drugs and it results in much better long-term outcomes than if they are treated and substantial financial savings as well.21
Antipsychotics increase the risk of dying substantially through a variety of mechanisms, which include suicide, cardiac arrhythmias, diabetes and major weight gains.9
The drug companies have caused tremendous harm by their widespread illegal and aggressive promotion of the drugs for off-label use (see Chapter 3). The legal use is also increasing, e.g. in children, the use of antipsychotics went up eight-fold between 1993–1998 and 2005–2009, and it doubled in adults.62
The story of antipsychotics has many similarities to that of the SSRIs. The clinical research wasn’t aimed at clarifying the role of the new drugs for clinicians and patients but was driven by marketing strategy, and new drugs were much hyped although large, independent government-funded trials found they weren’t better than old drugs63,64,65 (see also Chapter 9). A trial of 498 patients with a first-episode schizophrenia found no difference in discontinuation rates between four newer drugs and haloperidol.65 Discontinuation rate is a sound outcome, as it combines perceptions of benefits and harms of the drugs. The study was funded by three drug companies but they were kept at arm’s length.
Antipsychotics are standard treatment for bipolar disorder, which is mainly iatrogenic, caused by SSRIs and ADHD drugs, and they are also used for depression when treatment with an antidepressant is not enough. We now see advertisements, e.g. for AstraZeneca, about combination therapy for depression, and there are even preparations that combine the drugs in the same pill, e.g. Symbyax from Lilly, which contains Prozac (fluoxetine) and Zyprexa (olanzapine),48 two of the worst psychotropic drugs ever invented.
Like for the SSRIs, there are many perverse trials supporting antipsychotics for virtually everything. In 2011, an AstraZeneca trial studying whether quetiapine could prevent the development of psychosis in people as young as 15 years ‘at risk’ of psychosis was stopped after protests that it was unethical.66 There is no good reason to believe that these drugs can prevent psychosis, in fact, they cause psychosis in the long run (see above);21 and most people ‘at risk’ would never have developed psychosis.
A 2009 meta-analysis of 150 trials with 21 533 patients showed that psychiatrists had been duped for 20 years.63,67 The drug industry invented catchy but entirely misleading terms such as ‘second generation antipsychotics’ and ‘atypical antipsychotics’, but there is nothing special about the new drugs, and as they are widely heterogeneous, it’s wrong to divide them into two classes.
It’s remarkable that it was possible to show in a meta-analysis of published trials that new drugs aren’t better than old ones, as the research literature is so flawed. Haloperidol is the comparator in most of the trials, and their design is often flawed, using too high doses or too quick dose increases for haloperidol and other old drugs, resulting in a false claim that a new drug is similarly effective but better tolerated.68 An analysis of 2000 trials in schizophrenia revealed a disaster area of poor-quality research that didn’t even improve over time, and with 640 different instruments to measure the outcome; 369 of these mostly homemade scales were only used once!69
Unsurprisingly, an internal Pfizer memorandum shows that the flaws are introduced deliberately:70
If we were going to have to increase dothiepin dosage from 75 mg to 100 mg, we should do so at 1 week rather than at 2 weeks, which would result in a high drop-out rate on dothiepin due to side effects. By 2 weeks, patients have learnt to live with side effects.
Zyprexa, another terrible Eli Lilly drug turned into a blockbuster
The deceptions worked, as always. Everybody wants a ‘modern’ drug, whatever that means, and this bad habit is extremely costly, even when the ‘modern’ drug is only an old drug in disguise. Olanzapine was an old substance and the patent was running out, but Lilly got a new patent by showing that it produced less elevation of cholesterol in dogs than a never-marketed drug!9 This was totally ludicrous, and in fact, olanzapine raises cholesterol more than most other drugs. It could therefore have been marketed as a cholesterol-raising drug, but that wouldn’t have made Zyprexa a blockbuster with sales of around $5 billion per year for more than a decade.9
A Cochrane review from 2005 reported that the largest trial with olanzapine had been published 142 times in papers and conference abstracts.71 I am not kidding, it was the same trial in 142 publications. The carpet bombing also included criminal activities (see Chapter 3), and the aggressive marketing made Zyprexa the most widely used antipsychotic drug in the world, although it isn’t any better than far cheaper alternatives. In 2005, Zyprexa was Lilly’s top-selling drug at $4.2 billion.72
Money, marketing and lies ensured that doctors didn’t use the old cheap drugs. In 2002, the sales of Zyprexa were 54 times larger than the sales for haloperidol in Denmark, amounting to a staggering €30 million a year, although our country is very small. There was no excuse for this. Two years earlier, a meta-analysis was published in the BMJ that concluded that ‘the new drugs have no unequivocal advantages for first line use’.73
The last time I checked the price for Zyprexa, it cost seven times as much as haloperidol. It’s irresponsible to waste so much money, and patient organisations contribute to this. They only know what the drug firms have told them, or what the psychiatrists have told them, which is about the same, as the psychiatrists also generally only know what the drug firms have told them. It was therefore not surprising when the chairman of an organisation for psychiatric patients in 2001 called it unethical that Danish psychiatrists in her view were too slow to use the newer antipsychotics such as Zyprexa and Risperdal (risperidone).74 A researcher explained that many patients on Zyprexa increased their body weight by 15–25 kg during a few months, that there was a risk of diabetes, and that increased cholesterol was commonly seen. He also commented on the adverse effects of Risperdal and said that the likely reason that the chairman wanted these drugs to be used much more was that the adv
erse effects were little known. Wise words indeed.
In Chapter 3, I described that Lilly agreed to pay more than $1.4 billion for illegal marketing for numerous off-label uses including Alzheimer’s, depression and dementia, and Zyprexa was pushed particularly hard in children and the elderly, although the harms of the drug are substantial, inducing heart failure, pneumonia, considerable weight gain and diabetes.75 In 2006, internal Lilly documents were leaked to the New York Times, which demonstrate the extent to which the company downplayed the risks of its drug.72,76 Lilly’s chief scientist, Alan Breier, told employees in 1999 that ‘weight gain and possible hyperglycemia is a major threat to the long-term success of this critically important molecule’, but the company didn’t discuss with outsiders that a 1999 study, disclosed in the documents, found that blood sugar levels in the patients increased steadily for 3 years.76 Lilly instigated legal action against a number of doctors, lawyers, journalists and activists to stop them from publishing the incriminating leaked documents on the internet, and after the injunction, they disappeared.
In 2007, Lilly still maintained that ‘numerous studies … have not found that Zyprexa causes diabetes’, even though Zyprexa and similar drugs since 2003 on their label had carried an FDA warning that hyperglycaemia had been reported. Lilly’s own studies showed that 30% of the patients gained at least 10 kg in weight after a year on the drug, and both psychiatrists and endocrinologists said that Zyprexa caused many more patients to become diabetic than other drugs.76
Zyprexa is likely more harmful than many other antipsychotics.77 In 2001, Lilly’s best-selling antidepressant Prozac was running out of patent and the company was desperate to somehow fool people into using Zyprexa also for mood disorders and called it a mood-stabiliser rather than an antipsychotic. It doesn’t stabilise the mood, and it was also a challenge that general practitioners were worried about the harms of antipsychotics, but Lilly was determined to ‘change their paradigm’. The internal documents say it all. In psychiatry, it doesn’t really matter which drugs you have, as most drugs can be used more or less for everything, and psychiatrists are easily amenable for manipulation, even in the way they define and name their diseases.
Deadly Medicines and Organised Crime Page 40