Editor’s Note: Over the next several months, Mad in America is publishing a serialized version of Peter Gøtzsche’s book, Critical Psychiatry Textbook. In this blog, he discusses how cold-turkey withdrawal is mistaken for “relapse,” and how the largest drug companies have paid billions in fraud settlements related to these drugs. Each Monday, a new section of the book is published, and all chapters are archived here.
Psychosis pills do not prevent relapse
About length of treatment, one textbook noted that some patients will need lifelong drug treatment;16:222 another that most patients with schizophrenia will need lifelong treatment.17:657 This is clearly not true, which the results from Lapland demonstrate (see Chapter 7, Part Three).
The basis for this misconception is the so-called maintenance or continuation studies where patients in current treatment are randomised to continued treatment or placebo. Such studies cannot tell us if the patients still need the drug; they measure what the withdrawal effects are. But the psychiatrists conclude that the drugs reduce the risk of relapse17:314,19:236 because they mistake withdrawal effects for relapse.
One textbook claimed the dramatic result that if patients stop treatment early, there is up to an 85% risk of relapse while the risk is only 15% if the patients continue with the drug.17:315 There was no reference and it is unscientific to write “up to.” Evidence-based medicine is about what the effect is, on average, and one might as well write “down to,” which doctors never do when they speak about drug effects they perceive as positive.
One page earlier, the authors were more modest, saying that the risk of relapse is reduced by 60% but also that the risk is significantly less in studies of at least two years duration.17:314 They quoted a 2012 meta-analysis for this result.149
I could not find the 85% versus 15% anywhere in the huge literature I have on my computer or by searching on the Internet. The meta-analysis reported 64% versus 27% with relapse after one year, and 57% versus 22% independent of the duration of the study. Thus, the evidence-free claim of a 70% difference became only 37% and 35% in the meta-analysis.
The trials were flawed, as most patients on placebo were exposed to cold turkey withdrawal of their drug. The authors of the meta-analysis did a meta-regression with study duration as explanatory variable, which showed that the apparent effect of continued treatment with psychosis pills on relapse prevention decreased over time and was close to zero after three years.149
It is really bad medicine to keep the patients on their toxic drugs for years or lifelong based on the false belief that this improves their prognosis. When follow-up is longer than three years, it turns out that discontinuing psychosis pills is the best option. There is only one appropriately planned and conducted long-term maintenance trial, from Holland.192 It has seven years of follow-up, and patients who had their dose decreased or discontinued fared much better than those who continued taking drugs: 21 of 52 (40%) versus 9 of 51 (18%) (P = 0.02) had recovered from their first episode of schizophrenia.
We have highly convincing evidence that psychosis pills prevent patients from becoming cured (see Chapter 7, Part Three). And yet psychiatrists continue to recommend long-term treatment; many patients stay on the pills for many years; and many end up on disability pension. This is the upside-down world of psychiatry and one of many signs that the whole specialty should be disbanded to protect the patients (as I will explain in Chapter 16).
Danish researchers tried to repeat the Dutch study, but their study was abandoned because some patients were scared about what would happen if they did not continue with their drug while others wanted to come off it and did not want to be randomised to continuation. The key investigator was Nordentoft who quoted the meta-analysis of the maintenance studies. Since the Dutch study is highly important and was published in 2013, it is curious that she didn’t quote it.
There is another long-term study, from Hong Kong, published in 2018.193 The researchers treated first-episode patients with quetiapine for two years; discontinued the treatment in half of them by introducing placebo; and reported the results at 10 years. They found that a poor clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and in only 19 (21%) of 89 patients in the maintenance treatment group.
I immediately suspected that the trial was flawed, as this result was the exact opposite of the Dutch result, and that the investigators had tapered off the drug too quickly. As there was nothing about their tapering scheme in the article, I looked up an earlier publication, of the results at three years.194 They didn’t taper at all; all patients randomised to placebo were exposed to cold turkey withdrawal.
The 10-year report was revealing: “A post-hoc analysis suggested that the adverse consequences of early discontinuation were mediated in part through early relapse during the 1-year period following medication discontinuation.”193 In plain language: We doctors harmed half of our patients by throwing them into the hell of a cold turkey withdrawal.
The investigators defined a poor outcome as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. They called their trial double-blind, but it is impossible to maintain the blind in a trial with cold turkey symptoms, and it is highly subjective whether there are any persistent psychotic symptoms and whether clozapine should be given. It is much more relevant if the patients return to a normal life. A table showed that after 10 years, 69% of those who continued taking their drug were employed versus 71% in the cold turkey group, a remarkable result considering the iatrogenic harms inflicted on the latter group. As noted earlier, trials like this one are highly unethical because some patients commit suicide when they experience cold turkey effects.
Please think about this: Why would drugs that have no clinically relevant effects when used for acute psychosis suddenly have dramatic effects on relapse when they are withdrawn after a considerable period of time? This makes no sense. But that is what psychiatrists want us to believe.
There was very little information in the textbooks about how to withdraw the drugs slowly and safely. One book explained that, because there was an upregulation in number of receptors, a too-rapid dose decrease can elicit rebound psychosis, as downregulation is slow.16:221 This was an admission that maintenance studies are fatally flawed. The book recommended gradual tapering over several months but did not advise how.16:577
Only one textbook gave advice about tapering. It advised a dose reduction of 20% every six months but did not explain what this means.17:657 It could be 20% of the starting dose or 20% of the current dose. Thus, the dose reduction steps could be 80%, 60%, 40%, 20% and zero, which is a period of 2.5 years, or 80%, 64%, 51%, 41%, 33%, etc., in which case the withdrawal would take much longer. It is highly likely that what was advised was a linear taper, i.e. the first option, and not an exponential taper, as this is what psychiatrists routinely do.8,195 In addition, an exponential taper would have required information about what to do when the dose became low, as otherwise the taper would never stop.
Very few people know that a linear taper is wrong. As the binding curves for drugs to receptors are hyperbolic, the taper must be exponential (see the receptor occupancy curve for the depression pill citalopram, which I will present in Chapter 15).8
Since the binding curves are flat at the top and most patients are on a high dose, the initial dose reduction can often be relatively large without any ill effects. However, when the dose has become low, the reductions often need to be small because the curve is very steep at low doses. Most importantly, tapering is a highly individual process, as patients react very differently to the same dose reduction. It is therefore a trial and error process in each case.8:93
Organised crime and fraud pay off
The psychiatrists used industry jargon when discussing the different psychosis drugs. All textbooks talked about first- and second-generation psychosis pills;16:130,16:219,16:302,16:560,17:314,18:234,19:236,20:416 one also about third-generation pills; 18:234 some drugs were called atypicals;16:560 and some were called modern,18:116 which suggests that you are outlandish and not up-to-date if you prefer other drugs.
As the drugs within these classes are widely different in their effects, it is meaningless to divide them into two or three classes. Academics should do better than echoing the misleading terms the industry has invented, which help them sell pills that are far more expensive than pills that are not worse, and in some cases even better, as they have fewer serious harms.7
As an example, one textbook mentioned that olanzapine, even though it was called a second-generation drug, is not a first-choice drug due to its metabolic harms.20:418 But marketing beats science into a cocked hat. This drug, one of the worst psychotropic drugs ever invented, became a blockbuster, partly because of fraud, harassments via lawsuits against doctors, lawyers, journalists, and activists who wanted to tell the truth about the drug, and organised crime that included illegal marketing.6:31 I have estimated, based on sales and the published meta-analysis in people with dementia,162 that up to 2007, olanzapine had killed 200,000 patients.6:232
The story of olanzapine is a dire one, which students of psychiatry should know about. In 2001, Lilly’s best-selling depression pill Prozac (fluoxetine) was running out of patent. The company was desperate to somehow fool people into using olanzapine (Zyprexa) for mood disorders, so Lilly misleadingly called it a mood stabiliser.196 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!197 Olanzapine raises cholesterol more than most similar drugs and it should therefore have been marketed as a cholesterol-raising drug, but that wouldn’t have made it a blockbuster with sales of around $5 billion per year for more than a decade.197
A lawsuit revealed that Lilly’s documentation for the effect of olanzapine was so bad that the drug should not have been approved, but the FDA covered up for all Lilly’s manipulations, just as they did with fluoxetine (as I will explain in Chapter 8).198 A highly revealing book, The Zyprexa Papers, by lawyer Jim Gottstein, describes illegal, forced drugging that destroyed patients.199 Psychiatrists, lawyers, and Eli Lilly lied shamelessly, and judges didn’t care, which I experienced first-hand as Gottstein’s expert witness. Gottstein needed to go to the Supreme Court in Alaska before he got any justice, and he ran a great personal risk by exposing Lilly documents that were supposed to be secret.
One of the reasons why marketing of medicines is so effective is that the salespeople believe they are selling a very good drug. But they have been lied to by their bosses.6 Lilly’s huge commercial success with both fluoxetine and olanzapine illustrates that in psychiatry it doesn’t matter which drugs you have. Corruption, marketing, and lies will ensure that doctors don’t use better and cheaper drugs. And patient organisations willingly contribute to the corruption. They often receive money from the industry and they only know what the drug firms have told them, or what the psychiatrists have told them, which is the same, as they also get their knowledge from the industry. 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 psychosis pills such as olanzapine and risperidone.200
The crimes were massive. In 2009, Lilly agreed to pay more than $1.4 billion for illegal marketing for numerous off-label uses, including depression and dementia, and Zyprexa was pushed particularly hard in children and the elderly.201 The allegations were raised by six whistle-blowers from Lilly who were fired or forced to resign by the company. According to the complaint, one sales representative had contacted the company hotline regarding unethical sales practices but received no response.
Lilly salespeople were posed as persons in the audience who were interested in Zyprexa’s expanded use and asked planted questions during off-label lectures and audio conferences for physicians. Another tactic was that, while knowing the substantial risk for weight gain posed by Zyprexa, the company minimised the connection between Zyprexa and weight gain in a widely disseminated videotape called “The Myth of Diabetes.”
The fraud was massive. In 2007, Lilly still maintained that “numerous studies … have not found that Zyprexa causes diabetes,” even though Zyprexa and similar drugs have carried an FDA warning on their labels that hyperglycaemia had been reported since 2003.202 Lilly’s own studies showed that 16% of the patients gained at least 30 kg in weight after a year on the drug, and both psychiatrists and endocrinologists said Zyprexa caused many more patients to become diabetic than other drugs. But Lilly and corrupt psychiatrists produced papers describing schizophrenia as a risk factor for diabetes!4 As always, the drug wasn’t the problem; it was the disease.
Zyprexa seems to be more harmful than many other psychosis pills.196 But Lilly prepared fictitious patient stories for use by the sales force.196
An internal AstraZeneca email said that Lilly runs a large and highly effective investigator-initiated trials programme; they offer significant financial support but want control of the data in return; they are able to spin the same data in many different ways through an effective publications team; and negative data usually remains well hidden.203
Organised crime and fraud is also the business model for other companies.6:22 AstraZeneca silenced a trial that showed that quetiapine (Seroquel) led to high rates of treatment discontinuations and significant weight increases, while the company at the same time presented data at European and US meetings that indicated that the drug helped psychotic patients lose weight.204 Speakers’ slide kits and at least one journal article stated that quetiapine didn’t increase body weight, while internal data showed that 18% of the patients had a weight gain of at least 7%.196
In 2010, AstraZeneca accepted to pay $520 million to settle a fraud case after the company illegally marketed quetiapine to children, the elderly, veterans, and inmates for uses not approved by the FDA, including aggression, anger management, anxiety, ADHD, dementia, depression, mood disorder, post-traumatic stress disorder, and sleeplessness.205 The company also paid kickbacks to doctors.
In 2012, Johnson & Johnson was fined more than $1.1 billion after a jury found that the company and its subsidiary Janssen had downplayed and hidden risks caused by risperidone (Risperdal).206 The judge found nearly 240,000 violations under Arkansas’ Medicaid-fraud law. Janssen lied about the serious harms of risperidone, which include death, strokes, seizures, weight gain, and diabetes, and claimed the drug was effective and safe in the elderly. The crimes hit hard also on children.207 More than a quarter of Risperdal’s use was in children and adolescents, including nonapproved indications, and a panel of federal drug experts concluded that the drug was used far too much. A world-renowned child psychiatrist, Joseph Biederman from Harvard, pushed the drug heavily to children and also extorted the company. Internal emails revealed that Biederman was furious after Johnson & Johnson rejected a request he had made to receive a $280,000 research grant. A company spokesperson wrote that he had never seen someone so angry and that, since that time, their business had become non-existent within Biederman’s area of control.
It seemed that Alex Gorsky, Vice President of Marketing, was actively involved and had first-hand knowledge of the fraud and kickbacks.208 Johnson & Johnson’s board of directors rewarded Gorsky by selecting him to be the next CEO. Just like in the mob: the greater the crime, the greater the advancement.
A disproportionate number of the drug companies’ criminal activities involved psychiatric drugs and included illegal marketing, Medicare and Medicaid fraud, bribery of doctors, civil servants and politicians right up to the ministerial level, and disposal of evidence.6 The corruption of doctors is also worse than in any other specialty.7:267,209
Our academic institutions have also become corrupt. They grant ownership to the collected data to the sponsor and often accept that the doctors will have little influence on any publications.210 The competition for research funds means that companies can shop around among the various academic centres and choose those that don’t raise uncomfortable questions.
To see the list of all references cited, click here.
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I feel extremely hopeful while reading this. Knowledge can be used for saving human lives and for preventing hurting others. If everyone knew that medicines that target the nervous system have strong withdrawal symptoms and those symptoms would be recognized world wide and that slow exponential (or logarithmic?) tapering would be always used instead of fast linear reductions, then the world would be a much less dangerous place to live.
I have one big question: How could we prevent the constant flow of dangerous misinformation?
For millions producing it is their daily work. Is reasoning and documenting errors enough or should we make changes to how the scientific community and peer reviewing process works to enable self correcting or plan their motivations or provide more economical and political freedom for scientists or restructure decision hierarchies or something else?
Those that are currently doing harmful work and spreading dangerous nonsense and making poor decisions and wasting money as authoritarian figures that are trusted should somehow be reformed to serve the community and do something useful.