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 network meta-analyses spin the data on antidepressants, especially when financed by the pharmaceutical industry. Each Monday, a new section of the book is published, and all chapters are archived here.
The different treatments and combinations
In case of insufficient response in patients with depression or anxiety, one textbook suggested adding another drug (so-called augmentation), e.g. mirtazapine in the evening if the patient cannot sleep.17:661 It noted that augmentation with lithium, thyroxine, or lamotrigine is reserved for doctors with particular experience, and it suggested that a depression pill can be combined with a psychosis pill and that it is often a problem that the patients are underdosed. This advice increases drug harms for no benefit.
The literature is full of studies and meta-analyses claiming that some depression pills are better than others. Almost all of them are financed by the drug industry, either directly or indirectly. Many of the academic authors are on industry payroll as advisors, consultants, or lecturers and have little to do with writing the manuscript but just lend their well-known names to it.2,6,7 This is called guest authorship and those who write the manuscript are often ghost authors, as their names are not in the byline.140 When a person is acknowledged for her help without specifying for what, or is thanked for “editorial assistance,” this person is usually the real author of the paper.
I shall mention a recent network meta-analysis by Cipriani and colleagues, as it got enormous attention in the media. It was published in 2018 in The Lancet,271 which many consider a highly prestigious journal. The authors included 522 trials but by far most of the data came from published trial reports. They reported an effect size of 0.30 for drugs compared to placebo, very similar to earlier meta-analyses.268,269
However, even though they found an effect that is far below what is clinically relevant (see Chapter 8, Part One), they ranked the drugs according to their effect (response rate) and acceptability (drop-out for any reason), which were the two primary outcomes.
This is futile, and when I first saw this network meta-analysis, my immediate thought was that the authors had rewarded those companies that had cheated the most with their trials, as I indicated in the title when I published my observations.456 My suspicion was strengthened when I looked at the results in the abstract. The authors claimed that in head-to-head trials, agomelatine, escitalopram, and vortioxetine are more effective than other drugs and that these drugs are also better tolerated than other drugs. One doesn’t need to be a clinical pharmacologist to know that this is extremely unlikely to be true. I therefore took a closer look at the three drugs.
Agomelatine was touted in Lancet as being an outstanding drug by two authors,457 one of which was the Australian psychiatrist Ian Hickie who had numerous financial conflicts of interest. They claimed that fewer patients relapsed on agomelatine (24%) than on placebo (50%), but a systematic review by other psychiatrists found no effect on relapse prevention; no effect as evaluated on the Hamilton scale; and also that none of the negative trials had been published.458 Three pages of letters—which is extraordinary—in Lancet pointed out the many flaws in Hickie’s review.
Escitalopram and vortioxetine are sold by Lundbeck. It is far-fetched to believe that escitalopram can be better than citalopram because the active substance is the same. As already noted, citalopram is a stereoisomer consisting of an active part and an inactive mirror molecule, and escitalopram only contains the active substance.
When studied by Lundbeck in its own head-to-head trials, and meta-analysed under Lundbeck’s control, with Jack M Gorman as first author, the active molecule was better than itself.459 All three authors of the meta-analysis worked for Forest, Lundbeck’s US partner, one as a consultant and the other two in the company.7:224 What are we supposed to make out of a paper published in a bought supplement to a journal which, on top of this, was edited by a person—the first author of the paper6—who was also bought by the company?459 Absolutely nothing.
Even if Lundbeck’s meta-analysis of its own trials is believed, there were no relevant differences between the parent drug and the “me-again” drug.7:225,460 Four independent reviews of the evidence—by the FDA, the American advisory group Micromedex, the Stockholm Medical Council, and the Danish Institute for Rational Drug Therapy—all concluded that escitalopram offers no significant benefit over its mother molecule.461
The Cochrane review of escitalopram is disgraceful. It is from 2009 and has not been updated even though what it says is totally misleading: “Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93).”462 It’s first author is Andrea Cipriani who was also behind the untrustworthy network meta-analyses of depression pills published in The Lancet.
The official task of the government-funded Institute for Rational Drug Therapy is to inform Danish doctors about drugs in an evidence-based fashion. In 2002, the institute noted that escitalopram didn’t have clear advantages over the old drug.463 Lundbeck complained loudly about this in the press and said it was beyond the institute’s competence to give statements that could affect the international competition and damage Danish drug exports.464 It wasn’t beyond the institute’s competence, but the institute was reprimanded by the Minister of Health, Lars Løkke Rasmussen, who later became Prime Minister. Our highly praised governmental institute was only allowed to tell the truth about imported drugs, not about drugs we export. Principles are only valid if they don’t cost too much.
Two years later, the institute announced that escitalopram was better than citalopram and might be tried if the effect of citalopram hadn’t been satisfactory.465 The institute must have stepped on its toes to find a politically correct way to express themselves.466
I had a big laugh when I saw the four references in support of the positive statements.7:226 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. Desperate for finding an appropriate answer, she said: “Yes, if a patient is about to throw herself out the window!” This was doubly ironic, as SSRIs increase the risk of suicide.
In 2003, Lundbeck breached the UK industry code of practice in its advertising on five counts, notably by claiming that “Cipralex [escitalopram] is significantly more effective than Cipramil [citalopram] in treating depression.”461 Lundbeck also attributed harms to citalopram in its literature on escitalopram that weren’t mentioned in promotional material for citalopram. This confirmed the adage that it’s surprising how quickly a good drug becomes a bad drug when the patent expires.
In 2013, the European Commission imposed a fine of €94 million on Lundbeck and fines totalling €52 million on several producers of generic citalopram, which, in return for cash, had agreed with Lundbeck in 2002 to delay market entry of the drug in violation of EU antitrust rules.467 Lundbeck had also purchased generics’ stock for the sole purpose of destroying it.
When independent researchers made a meta-analysis based on indirect comparisons, escitalopram vs placebo, and citalopram vs placebo, there was no difference.468 Their results are telling. For the adjusted indirect comparison of 10 citalopram and 12 escitalopram placebo-controlled trials (2,984 and 3,777 patients, respectively), escitalopram wasn’t any better than citalopram, indirect OR 1.03 (0.82 to 1.30). The researchers also did a meta-analysis of seven head-to-head trials (2,174 patients), and the efficacy was now significantly better for escitalopram than for citalopram, odds ratio 1.60 (1.05 to 2.46). A similar discrepancy was found for treatment acceptability.
Such results tell us we should distrust network meta-analyses of depression pills. The cheating is pervasive and obvious. A drug containing the same active substance as the molecule that is out-of-patent is claimed to be more effective and better tolerated. How dumb does Lundbeck think doctors are? Very dumb, indeed. Lundbeck made the rejuvenated drug a commercial success via a huge fraud scheme where the outcomes of the trials were already established before the trials were begun.6:229
When Lundbeck’s American partner Forest had performed a trial of citalopram for compulsive shopping disorder, Gorman appeared as an expert on Good Morning America and said that 80% of the compulsive shoppers had slowed their purchases on the drug.131 The viewers were told that this new disorder could affect as many as 20 million Americans, of which 90% were women.
In 2010, Forest pleaded guilty for obstruction of justice and illegal promotion of citalopram and escitalopram for use in treating children and adolescents with depression.469 Forest agreed to pay over $300 million to resolve criminal and civil liability arising from these matters and faced numerous court cases from parents to children who had either committed suicide or had tried.470
Forest lied to Congress and kept negative trials out of public view.469,471,472 Forest had 19,000 so-called advisory board members,472 and the periodical Pharmaceutical Marketing has provided the answer as to why so many advisors are needed:473
The advisory process is one of the most powerful means of getting close to people and of influencing them. Not only does it help shape medical education overall, it can help in the process of evaluating how individuals can best be used, motivate them to want to work with you—and with subliminal selling of key messages ongoing all the while.
The most important of these corrupt doctors are paid obscene amounts of money for doing very little or nothing.6:78 A professor of psychiatry stated:
“‘It is very dismaying to find academic psychiatrists that one has hitherto respected supporting one drug on a Monday and another on Tuesday … I can think of a well-known British psychiatrist I met and I said, ‘How are you?’ He said, ‘What day is it? I’m just working out what drug I’m supporting today.’”341,369
The generous honoraria for lectures attract a large army of physician “educators.” A 2002 survey found that American psychiatrists were paid about $3,000 for a symposium lecture and some earned as much as $10,000.369 Doctors working for multiple companies are called drug whores by drug reps,343 and their work as lecturers or advisors are sometimes used as “payback” for participation in trials, which allows the doctors to say that they had no financial conflicts of interest while doing the trial.474
A psychiatrist reported how generous Wyeth was when he sold its drug, venlafaxine (Effexor), to colleagues:475
We were all handed envelopes as we left the conference room. Inside were checks for $750. It was time to enjoy ourselves in the city … Receiving $750 checks for chatting with some doctors during a lunch break was such easy money that it left me giddy. Like an addiction, it was very hard to give up.
When he said at a lecture that other drugs might be equally effective as Effexor, he was immediately visited by Wyeth’s district manager who asked him if he had been sick. The doctor salesman then abandoned his lucrative career as an academic prostitute on top of his private practice.
Forest 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. Lundbeck’s reaction to the crimes was: “We know Forest is a decent and ethically responsible firm and we are therefore certain that this is an isolated error.”470 Of course. In the eyes of those who collect the cash,471 organised crime is “an isolated error.”
The corruption was total. Forest recruited about 2,000 drug pushers (psychiatrists and primary care physicians) whom the company trained to “serve as faculty for the Lexapro Speakers’ Bureau Program.”476 It was obligatory that speakers used the slide kit prepared by Forest. Forest provided “unrestricted grants” to professional societies, including the American Psychiatric Association, so that they could develop “reasonable practice” guidelines, and 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.
Vortioxetine seems to be an exceptionally poor drug. Every author in all of the published short-term trials had significant commercial ties to Lundbeck, which is a sure way for a company to control that what gets published supports its marketing ambitions. But when independent researchers compared vortioxetine with duloxetine and venlafaxine in meta-analyses, they found that these drugs were significantly more effective than vortioxetine at three of the four dose levels tested.477
It has been documented that network meta-analyses (NMA) of published trial data are unreliable. In an elegant study of this, the authors used data from 74 FDA-registered placebo-controlled trials of 12 depression pills and their 51 matching publications.478 For each dataset, NMA was used to estimate the effect sizes for 66 possible pair-wise comparisons of these 12 drugs. To assess how reporting bias affecting only one drug may affect the ranking of all drugs, the researchers performed 12 different NMAs where they used published data for one drug and FDA data for the 11 other drugs. They found that the effect sizes for drugs derived from the NMA of published data versus those from the FDA data differed in absolute value by at least 100% in 30 of 66 pair-wise comparisons. This is a huge bias.
The Lancet NMA by Cipriani et al. contained nothing new and what was claimed to be new was unreliable. However, Cipriani hyped the paper to the extreme, e.g. in BBC News:479
This study is the final answer to a long-standing controversy about whether anti-depressants work for depression … Scientists say they have settled one of medicine’s biggest debates after a huge study found that anti-depressants work. The study … showed big differences in how effective each drug is … The authors of the report … said it showed many more people could benefit from the drugs … The Royal College of Psychiatrists said the study “finally puts to bed the controversy on anti-depressants” … Researchers added … at least one million more people in the UK would benefit from treatments, including anti-depressants.
The mean baseline severity score on the Hamilton Depression Rating Scale was 25.7, which is considered very severe depression.270 Thus, it was confirmed once again that the oft-heard claim that these drugs work for very severe depression is wrong, as the average effect was far below the minimal clinically relevant difference.
The NMA did not report the average drop-out rate for the drugs, but it was very close to 1, which is also a misleading result. As noted above, when my research group used the clinical study reports from the European drug regulators, we found 12% more drop-outs on drug than on placebo (P < 0.00001), so if one million more people in the UK should benefit, the treatment should be placebo.301
Later, my research group showed that the outcome data reported in Lancet differed from the clinical study reports in 12 of the 19 trials they examined.480
The Lancet meta-analysis was garbage in, garbage out, to an unusual degree, which is surprising considering who the authors were. Among Cipriani’s 17 co-authors were two with whom I have published the guidelines for reporting network meta-analyses,217 and a third author was Cochrane statistician Julian Higgins, editor of the Cochrane Handbook of Systematic Reviews of Interventions that describes, over 636 pages, how do to Cochrane reviews.481 This suggests that some of the most experienced co-authors did not contribute much to the paper. None of these three people were among the 12 authors who selected the articles and extracted the data, four of whom declared they had received money from drug companies.
In Denmark, the NMA was hyped to the extreme on the homepage of one of the five regions, which referred to a newspaper article:482
The conclusion is clear: Antidepressants work. And those who did the study assert that some antidepressants work better than others. One of those ’happy pills’ which can best alleviate the depression is, for example, Cipralex.
Of course. Cipralex contains escitalopram, marketed by Lundbeck, and the Danish drug export is the largest source of national income. It beats agriculture although we have four pigs for every citizen, and also have pig farms abroad, e.g. in Spain.
Not only the Cochrane authors but also Poul Videbech functioned as Lundbeck’s useful idiots. Videbech praised the NMA in the most bizarre way.482 He noted that the “very large study” was “far more credible” than a Danish study published a year earlier,112 which he claimed concluded that the drugs have no significant effect. He also claimed that Cipriani had taken into account the sources of error that the Danish researchers had not been aware of.
As so often before, which is also clear in the textbook he edited,18 Videbech was highly manipulative. First, there were no errors in the Danish meta-analysis by Jakobsen et al., which was exemplary and highly rigorous, and Cipriani et al. did not point to any errors. They did not even cite the Danish meta-analysis, although it was published 12 months before their own.
Second, the NMA was far less credible than the Danish meta-analysis that only included comparisons with placebo, which is the reason for the smaller number of patients. As already noted, head-to-head comparisons are notoriously unreliable and they are not research but marketing disguised as research.6,7
Third, it is false that the Danish meta-analysis did not find a significant effect of the pills. The effect was highly significant (P < 0.00001), which the researchers reported.
Fourth, the effect in the Danish meta-analysis was about the same as that found in the NMA; the effect sizes were 0.26 and 0.30, respectively.
The main difference between the two meta-analyses was how the researchers interpreted their results. In their abstract, Jakobsen et al. concluded:
SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.
In contrast, Cipriani et al. concluded: “All antidepressants were more efficacious than placebo in adults with major depressive disorder,” with no caveats about the risk of bias and absolutely nothing about the drugs’ harms. The only thing they reported was the proportion of patients who dropped out early because of adverse events, which was higher for all active drugs than for placebo.
This whole affair was hugely embarrassing for Cipriani et al., for Cochrane, and for Lancet. Cipriani’s two NMAs in depression, one for adults271 and one for children and adolescents297 (see Chapter 8, Part Four), and numerous other meta-analyses, e.g. virtually all Cochrane reviews, are seriously biased and should be distrusted. This is the indisputable conclusion when we compare with the results obtained in studies based on clinical study reports submitted to drug regulators.279,300,314,315,326,378
This important message was not in the textbooks. Leading psychiatrists do not want to hear the truth about psychiatric drugs. They prefer to be fooled by the drug industry and corrupt colleagues and to propagate false statements about the drugs in their textbooks and elsewhere.
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To see the list of all references cited, click here.
