Why Most New Antidepressants Are Ineffective
I posted the commentary “Why Most New Antidepressants Are Ineffective” around 2005. I have received several messages from eminent professors who have seen it and complimented me on it, which is most gratifying.
The medical profession should be ashamed that, half a decade down the track, is has done woefully little to correct the situation. Consumer demand, if it can be mobilised, has the power to do that. But people must “vote” and act.
We now hear that many companies are cutting back or ceasing funding of all/most psychotropic drug development. My immediate reaction is that hardly matters, since they only contributed a small share to research anyway, like barely 10%, e.g. see Light & Morgan (1, 2), for discussion and an independent estimate. Most major advances occur by serendipity, not by direct research. Meanwhile, to update matters relating to Pharmaceutical company influence and bias, and comment about it, see refs and read Angell’s piece in the 2009 NY book review Marcia Angell (3).
Fifty years on and ‘Plus ça change, plus c’est la même chose’. As Avorn reminds us (4), exerpted: “An unsigned 1961 Journal editorial titled “Ethical Drugs — Who Shall Educate the Physician?” noted with concern that “manufacturers spend about four times as much on the promotion of drugs as the total cost of running all the medical schools.”
I have made some small changes to the original text and added a few pertinent references:
I am a lifelong pharmacologist, my professional life as a ‘psychiatrist’ (I actually prefer to be called a clinical neuro-pharmacologist) has been spent treating depressive illnesses that require drugs. I have published a number of original papers on psychopharmacology in prestigious scientific journals (none of my papers have had any connection with, or funding from, pharmaceutical companies). No-one can typify me as an anti-drug lobbyist with a fringe anti-medicine agenda. However, the situation that I see, as I teeter on the brink of ‘retirement’, is that doctors have been hoodwinked into using drugs that just do not work, and that doctors and medical science itself have been corrupted with some very serious problems that will require radical intervention to remedy. for instance, by drastically changing the dreadful DSM cook-book. But then one could say more fool the other countries for slavishly adopting it. I am proud to say I never did.
Most people who read this can help to change things, so read on, and I will explain how.
Most of the new antidepressant drugs introduced in the last twenty years do not work effectively. The evidence about them presented to doctors, even in the most respected leading medical journals, is closer to advertising copy than it is to science. There is clear and incontrovertible evidence that scientific data and publications are controlled, manipulated and subverted by international pharmaceutical companies to an extent that would astonish most ordinary people, including doctors. Indeed the situation has precipitated the resignation of the editor of the British Medical Journal (BMJ). It is also clear that large numbers of famous and influential doctors have put their names to ‘scientific papers’ that have been written by professional copy writers employed by pharmaceutical companies (‘ghost writing’) with the doctors names (after nefarious favours, and transferring of greenbacks) added for credibility. A formal study now confirms this for randomised trials (5). In my opinion review articles may be safely assumed to be even more partisan. The Lancet editor, Richard Horton, gave evidence to the UK parliamentary inquiry in 2004 about drugs and the pharmaceutical industry (Select Committee on Health), you may look at the original at the UK Parliament web site:
In this evidence to the select committee Horton started by stating
‘At present, our population is part of a largely unregulated experiment involving poorly investigated new medicines that have been licensed on the basis of insufficient data.’
The evidence provided to the same select committee by Professor Andrew Herxheimer (6) is also a must read. http://www.parliament.the-stationery-office.co.uk/pa/cm200405/cmselect/cmhealth/42/4101401.htm
I suggest everyone should be alarmed when men of their position and stature make such statements to a parliamentary select committee. Follow the link, and read at least some of the evidence for yourself. You will rarely locate a more plausible and reliable source of 24 carat information. A few further quotes from Horton’s evidence about drugs and pharmaceutical companies are relevant here (he made 10 major points).
… ‘Doctors were seriously and deliberately misled. This is not an uncommon practice’.
… ‘Hiding negative data: The classic recent example concerned Paxil (GlaxoSmithKline). The hidden trials showed a pattern suggesting limited efficacy of the drug and risks of potentially fatal adverse effects. The available published evidence indicated a very different story.’
‘… But the continuing privatisation of much of science (science in the service of wealth creation rather than health improvement) threatens to make independent research almost impossible to do.’
‘… Ghost-writing: It is standard operating procedure for pharmaceutical companies to seed the medical literature with ghost-written editorials, reviews, and opinion pieces emphasising off-label indications of licensed drugs. These papers are commissioned to a specific marketing-driven brief and are written by non-specialists. A company friendly expert is then paid to have his or her name appear on the article, facilitating publication in a respected journal and thus enhancing the impact of the message.’
He concludes by stating: ‘The compromised integrity of medicine’s knowledge base should be a serious concern to politicians and public alike.It is surprising and disappointing that this danger does not seem a serious priority within medicine itself.’
Please pause and remember and think: the above information is not from a crank rant, it is the Lancet editor, Horton, giving evidence to the UK Parliamentary select committee. Some pharmaceutical companies have exerted themselves persuading certain individuals that I am a ‘rat-bag’ (because of the critical essays and information on my web site, and some of my scientific publications), but achieving the same result with Horton, Angell and the many others who agree on these issues, will prove a more exciting and taxing challenge for them.
The ‘World Association of Medical Editors’ (WAME) http://www.wame.org/ have issued a recent statement (7), ‘Ghost Writing Initiated by Commercial Companies’. It states: ‘WAME considers ghost authorship dishonest and unacceptable’. That seems to me to be quite straightforward and unequivocal, which is unusual and refreshing in public debate nowadays! See:
Pharmaceutical companies justify their record profits by emphasising the cost of developing new drugs, yet the figures indicate that they only spend 10% on ‘Research and Development’ (R&D), but they spend 30% of their budget on advertising. Furthermore, a sizeable chunk of that meagre 10% includes expenses to doctors who do very little actual research, but attend briefings, conferences and the like that are thinly disguised junkets (I have colleagues who participate in such activities). So the proportion of the 10% that is true research is much smaller even than it seems. In reality most companies are almost certainly doing far more ‘development’, of publicly (taxpayer) funded original research, than original research of their own. My analysis and summation of the situation is that pharmaceutical companies have been persistently and systematically deceiving us all and misrepresenting what they do, and how they do it, to their great financial benefit and everyone else’s detriment. I expect some would argue that constitutes powerful evidence against the benefits of unregulated capitalist free enterprise: I find it hard to counter that argument. The main source of financial information concerning ‘Big Pharma’, i.e. pharmaceutical companies that I know of is Public Citizen Congress Watch (8) www.citizen.org/documents/Pharma_Report.pdf.
Another ex-editor of a major medical journal who has expressed opinions of note is Marcia Angell, former editor in chief of the prestigious ‘New England Journal of Medicine’ (NEJM). See also
where there is a précis of her informative, revealing and well received book (‘The Truth About the Drug Companies’) and other links.
Most ‘new’ antidepressant drugs (for the last 30 years) are not new at all, they are simply ‘me-too’ or ‘badge engineering’ drugs. They are marketed, not on scientific facts and medical merit, but with guile and often deceit (9-14). The ‘Spin Doctors’ orchestrate the performance, under the wing of pharmaceutical company executives who have law or business degrees, but little knowledge of science or medicine: the final call is probably by accountants who answer to the board and stockholders and who appear to endorse any means, fair or foul, in pursuit of the bottom line.
There are two main types of favourite new drug: ‘Me-too’ drugs are copies of another drug already marketed by someone else and intended to have the same mechanism of action and the same effects. ‘Badge engineering’ drugs are pharmacological copies of your own existing drug, that extend the patent, and are marketed as possessing an ‘improved’ mechanism of action and/or effects. Organon’s pair of ‘identical twins’, mianserin and mirtazapine, are the archetypal example, about which I have published a scientific paper, and written an account on my web site [link]. Such drugs are co-incidentally discovered, and understood to be better, at about the same time as the patent on the previous drug runs out. These are developments which artificially and dishonestly maintain prices, sales and profits for pharmaceutical companies, but rarely have benefits for anyone else, especially you and I, and our friends and loved-ones, all the actual recipients of these drugs as ‘patients’. I do hope the people who work for these companies, and their advertising agencies, never suffer the unpleasantness of being locked in untreated illness because they have been given one of their own drugs which does not work. However, statistics dictate that this must be happening frequently: irony, with a soupçon of justice?
When I first posted the evidence that mirtazapine does not posses the properties that are claimed for it, that was some few years ago, I received an e-mail from an ‘Organon’ person saying he was interested in my evidence, because he was beginning to have doubts about the drug himself. I do not suppose he still works there, but should he ever read this I would be interested to hear the sequel! Literate persons may be reminded of the old lines penned by John Donne, 400 years ago. I quote below the whole passage, because without it the full meaning of the shorter quotation, that is usually used (‘never send to know for whom the bell tolls, it tolls for thee’), is diminished.
‘No man is an island entire of itself; every man is a piece of the continent, a part of the main. If a clod be washed away by the sea, Europe is the less, as well as if a promontory were, as well as if a manor of thy friends or of thine own were. Any man’s death diminishes me, because I am involved in mankind. And therefore never send to know for whom the bell tolls, it tolls for thee’.
It is not only pharmaceutical companies that are culpable: it takes two to tango, and regrettably doctors have played a greater part in this process than is compatible with the professional and ethical standards the community might expect of them. As Jerry Kassirer, an editor of the New England Journal of Medicine argues, ‘the industry has deflected the moral compasses of many physicians’ (15). Doctors may be more interested in the gastronomic reputation of the venue that the sponsor chooses, rather than the ‘educational’ topic (guess who chooses the speaker, and prepares the slides?). Attending doctors prescribe newer more expensive drugs more frequently than other doctors (16), so it works. A growing number of observers are feeling uneasy about the proportion of doctors who fit this mould (17-22). Small wonder then that the current scandals over the ineffectiveness of many new drugs, including antidepressants, are refusing to go away. A constant stream of new revelations about everything from gifts to doctors, enormous payments (US$ 500,000 in one year to one doctor) to key opinion leaders (KOLs, to the trade), journal supplements that are ‘advertorials’, and outright deceit in research (9, 23), continue to assail us. It has reached the stage where a doctor trying to do the best for patients might feel perplexed about what to believe or who to trust.
Many western countries have embraced the ‘neo-liberal’ notion of devolvement of responsibilities and costs to non-government (i.e. industry) organizations that are charged with self-regulation. The funding of universities and medical research programs is now more commercialised, with the attendant pressure to produce results. He who pays the piper calls the tune. Other factors at the heart of these problems are the commercial pressures to maintain the circulation of Journals and the competitive marketing of drugs, which are often nearly identical (again, see Horton’s evidence).
A resumé of recent reports, all from four prominent journals (BMJ, Lancet, NEJM, JAMA) illustrates my point: and remember that I am a pharmacologist not an anti-drug lobbyist. Furthermore, note that the great majority of the references that I cite are from journals considered by everyone to be ‘first division’ and ‘mainstream’. The people making the comments I discuss, like Richard Smith, are not paranoid conspiracy theorists, but long-time pillars of the medical establishment. Smith, editor of the BMJ for 25 years, wrote that ‘Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies’ (24). Horton, of the Lancet, stated, ‘Journals have devolved into information laundering operations for the pharmaceutical industry’ (25), and Angell an NEJM editor said pharmaceutical companies were, ‘primarily a marketing machine … co-opting every institution that might stand in its way’ (26). The titles of these pieces convey the tone (I particularly like ‘McScience’). Everyone, especially doctors, will benefit from some understanding of the existing evidence of unscientific and disingenuous practices engaged in to produce favourable evidence about new drugs (9, 23, 27): if you think it is reliable and objective to fall back on meta-analysis studies (lots of similar studies ‘lumped’ together to produce bigger numbers) or practice guidelines, then think again. The evidence is that they are biased too, but in a more subtle and insidious way (6, 28-32). The so called ‘file draw effect’ (i.e. loosing unwanted results) is a prime example of distorted science and is relevant to the problem with the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Researchers using the freedom of information act in America have now discovered the (failed) trials of these drugs that were not ‘made available’ when applications to the FDA for licenses for them were being sought. This demonstrates that there were as many trials showing no effect as there are showing an effect (33): even the ones showing some effect show only a small effect on depression, insufficient (in my opinion) to even justify calling them antidepressants rather than anti-anxiety drugs (see previous ‘Psychopharmacology Update Notes’ e.g. citalopram).
There is persuasive (in my opinion, compelling) evidence that fudging of data by pharmaceutical companies is widespread. The paroxetine (Paxil etc) people have been accused of hiding suicides in their drug trials in order to show it in a more favourable light. (See also Horton’s evidence to the UK select committee).
Antidepressant drugs are still being ‘proved’ (a much used but misappropriated word) to work in trials, and then found not to work by ordinary clinicians, and patients (34). Longstanding readers of my ‘Psychopharmacology Update Notes’ will be aware that I have been opining the SSRIs are poor antidepressants for many years. The feedback I receive on my website sometimes contains indignant and angry comments, the gist of these is: ‘these drugs have been officially approved in all Western countries – how arrogant of you to say you know best and that they don’t work, … I use them all the time and I see lots of people getting better’.
How do we reconcile these apparently contradictory experiences and kinds of evidence? In fact it is surprisingly easy to do so, providing we appreciate one or two simple things about how science works, and about depression and its assessment. Depressive illness is difficult both to define and to measure, and the assessments used are subjective, and not true end points of illness outcome. Rather, they are interim proxy measures of improvement. It is well-established in science that proxy, or surrogate, outcome measures are unreliable unless their exact relationship to properly defined disease outcomes is firmly established (35-38). In the case of depression research their relationship to true disease outcomes is definitely not established. That means a typical 4 week long ‘double blind’ antidepressant drug trial stands a fair chance of showing a small difference (i.e. a bit better than placebo), but such results have little or no use or meaning except for gaining regulatory approval of drugs for pharmaceutical companies. Hence the results above with the FDA file drawer fiasco.
The other key point to remember is that a large proportion of the patients treated with antidepressant drugs do not suffer from drug responsive depressive illness. They are going to get better despite treatment, rather than because of it. This is exactly why double-blind placebo controlled trials are essential (but they are not sufficient in themselves) and the evidence for the above statement lies in the enormous placebo response rate in all these trials, making it difficult to distinguish drug responders from placebo responders, and swamping any meaningful results (39).
The ability of single antidepressant drug treatments to induce remission (i.e. complete wellness, as opposed to a small improvement) and prevent relapse is poor (40, 41). I do not mean that there are no effective antidepressant treatments, just that most individual new drugs are of low effectiveness when used by themselves. Furthermore, there is no demonstrated ability for SSRIs (or the TCAs) to prevent the outcome of death by suicide that effects 10 –15% of patients (42). The controversy concerning the possible increase in suicide rates in patients on SSRIs has led to analyses of pooled trial results. These demonstrate no difference between placebo and SSRIs in reducing the suicide rate following treatment (43, 44). That applies to the first month of treatment, and equally to the subsequent 5 months, when the suicide rate for trial participants is close to the untreated rate of 0.6% per annum, and also similar to suicide rates for those in the general population with major affective disorders (0.30%–0.80%). Those rates are both about 40 times more than the general population (0.016%) (45, 46). Reviewing these data reminds us that so far the new antidepressants have only been demonstrated to have a modest short-term effect on subjective rating scales, a modest ability to prevent relapse (47), and no long term influence on the important outcome of suicide (44). Of the patients who respond to initial treatment a significant proportion subsequently relapse, despite continued high dose treatment (48).
Melander specifically examined papers about SSRI trials and concluded, ‘… The degree of multiple publication, selective publication, and selective reporting differed between products. Thus, any attempt to recommend a specific selective serotonin reuptake inhibitor from the publicly available data only is likely to be based on biased evidence’. There are valid concerns that undue weight is being given to such biased evidence (49).
It is therefore futile and deceptive to rely on meta-analysis (lots of similar studies lumped together to produce bigger numbers) because these well known problems, biases and distortions can never be confidently discounted. As the computer boffins said years ago, ‘garbage in, garbage out’. Furthermore, Anderson’s meta-analysis demonstrated that pharmaceutical company sponsorship has a definite effect on apparent outcome, it accounted for as much of the effect size (improvement) as did any other variable (40). That accords with a review covering 37 general medical studies about sponsorship that concluded: ‘Aggregating the results of these articles showed a statistically significant association between industry sponsorship and pro-industry conclusions (50).
The independent replication of studies is an essential cornerstone of science. Remember the ‘cold fusion’ debacle? Widespread and persistent lack of independent replication is a crucial failing of the methodology of medical science. I have shown that applies to both animal and human research, e.g. the proposition and assumption that mirtazapine is a dual action drug (51) has been clearly demonstrated to be based on unreliable and unreplicated evidence, both in animal work (52), and human trials (53).
It has been shown that American research is very ‘amero-centric’. That is to say there is a heavy bias in North America to quoting papers from North America rather than papers (equally good, and dare I say often better) from Europe, or elsewhere. Such factors may explain why American Psychiatry is out of step with reality and dominated by the Diagnostic and Statistical Manual (DSM) produced by the American Psychiatric Association. The DSM seems to have more to do with justifying claims for reimbursement from insurance companies than it has to do with science. Shorter and Tyrer (now editor of the ‘British J of Psychiatry’) published a paper in the BMJ recently that throws light on the formation process of DSM and its relationship to pharmaceutical companies (54). In view of the prestige of both the authors and the journal I quote a key paragraph, unabridged:
“Industry has been busy behind the scenes in this handy convergence of eccentric new diagnoses and the market nicheing of compounds. For example, in May 1984, Robert Spitzer, the chief disease designer of DSM-III and DSM-III-R, convoked a meeting of the anxiety working group, cosponsored by “the Psychopharmacology Unit of the Division of Medical Affairs of the Upjohn Company.” At the end of the discussion of the relation between panic and agoraphobia, Spitzer announced, “Consensus favors the Upjohn model.” It is now routine for psychopharmacologists, such as Brown University’s Martin Keller, to receive as much as $500 000 (£320 000) in consulting fees from industry in a given year. USA Today has calculated that at 55% of the meetings of the various advisory committees of the FDA, “half or more of the FDA advisers had a conflict of interest”.”
Strong stuff indeed for a journal as staid and conservative as the BMJ.
Spitzer’s statement reported above, “Consensus favors the Upjohn model” sounds partisan. But worse than that it was, I suspect, arrogant and derisively dismissive. By now I trust readers are sufficiently questioning, sceptical and critical to anticipate the next piece of information: Upjohn, who sponsored the meeting, are the pharmaceutical company who make the benzodiazepine drug alprazolam (‘Xanax’), which is, of course, the main (officially approved) treatment for anxiety. How it can be perceived as proper or appropriate for them to be sponsoring such a meeting on disease classification is simply astonishing. There is no space here to discuss the close similarity of alprazolam to the infamous ‘triazolam’; that is a story worth reading for those with the energy and interest.
For many years I have referred to DSM as the ‘cook book’, so I was interested to hear a famous American psychiatrist who was deeply involved in DSM, Nancy Andreassen, using exactly the same phrase in a radio interview in 2006. This little rant is a relevant prelude to understanding that the influence of DSM has been to make the diagnosis of depression over-inclusive. It is probable that many patients diagnosed with major depression under that system would neither be so often diagnosed, nor so often treated with drugs, by many psychiatrists in other countries. Furthermore, there is a strong argument that it is an inappropriate diagnostic system, and that other approaches, that may be more successful in separating out the drug treatable illnesses, should be given greater consideration (34, 55-58). The key consequence, in relation to this essay, is that patients selected for drug trials using these criteria almost certainly contain so many inappropriate patients that the real beneficial effects of some effective drugs get lost in the noise.
The above understanding and analysis fits with various findings that show some drugs, like clomipramine, are more effective for severe depression, of that sort described by the labels ‘melancholic’ or ‘psychotic’. These analyses show that the old tricyclics (particularly clomipramine) and MAOIs and ECT are very probably more effective for these severe illnesses (59). In my firm opinion none of the new drugs, and that includes the supposed dual action drugs venlafaxine (Efexor) and duloxetine (Cymbalta), actually work as well clomipramine. So it seems that dual action drugs, or more accurately, mixtures of drugs aimed at achieving dual serotonin and noradrenaline reuptake inhibitor effects, are probably a promising way forwards. It is unlikely that a single drug will have an ideal ratio of potency of one effect versus the other, so it follows that a more flexible strategy is to use two separate drugs for this purpose (see essay on dual action drugs). That means it is much less likely that two such compatible drugs will be patented by the same company, and therefore the massive influence and promotional capability of pharmaceutical companies is not going to be brought to bear to promote such strategies. The reality of this distortion of practice and grass roots perception vs. performed (i.e. sponsored) research (there are very few trials of SNRI combinations) may be seen in the opinion of a panel of clinicians on augmentation strategies (60); the panel concluded “simultaneous targeting of both the noradrenergic and serotonergic systems is one of the most effective augmentation strategies”. Speaking as a clinician who has actually been using those strategies, almost exclusively, for the last 30 years, I can only comment, “well done guys, you’re getting there at last: better late than never”.
Adding lithium to an antidepressant is reported to be the most widespread first choice augmentation strategy; this puzzles me as the evidence is weak and practical experience is that it is a poor choice. We used it in London in the 1970s (61, 62), clomipramine + lithium + L-tryptophan was the ultimate mix, prior to progressing to tranylcypromine. After treating about 500 patients with lithium augmentation between 1976 and 1985 I gave up because it was no better than clomipramine alone, but more toxic and inconvenient. This leads me to suspect that lithium is helpful when added to non-serotonergic drugs, because it may be acting as a weakly serotonergic agent. It seemed to me to be more logical to progress immediately to an SNRI strategy, if the previous treatment was any TCA other than clomipramine.
The above wide ranging discussion is the required background for appreciating the rationale of dual-action strategies utilising two separate drugs to achieve that. The major remaining alternative drug treatment to remember is the old MAOIs, particularly tranylcypromine. Ironically, that is the one drug for which there is the very least amount of controlled trial evidence, yet the one drug that most experienced psychopharmacologists agree is indispensable for the treatment of severe illnesses. I would submit that this is yet another major example of the unhelpfulness of controlled trials of medication and the bias produced by pharmaceutical company sponsorship in the perceived relative effectiveness of treatments. In my opinion tranylcypromine is the most under-used antidepressant available. It is the one I would take, and the one I would give to my nearest and dearest, if any of us became ill. The supposed problems and ‘dangers’ of MAOIs are greatly exaggerated (see my information on MAOIs), In my opinion, to the point of hysteria.
I have subsequently published my review on MAOIs (63).
Is there anything you can do if you want to learn about what antidepressant treatment strategies actually do work? I suggest my essay on dual action antidepressants is a good place to start and my TCA review contains much valuable data on both TCAs and SNRIs (64).
Yes, many of you can. It is simple. Circulate this essay and the link to it (with appropriate attribution please) and these very simple recommendations (65, 66).
Changes could be achieved through simple action both by those who agree to participate in drug trials and by doctors, who could use their monopolistic power to promote, or even enforce, actions like:
- to cause to be set up independent research bodies that appoint appropriately qualified experts to design and conduct drug trials (65, 67)
- Pharmaceutical companies must never to allowed to exclusively collect, control and store trial data, it must always be under the control of the independent research bodies
- Facilitate the co-ordination of patient advocacy and support groups and unite them in their appreciation and action on these issues
- Develop strategies to thwart and uncover covert biased funding of internet sites by industry (classic Tabasco industry tactic)
- Researchers and doctors should not collude by performing refereeing services for Journals that do not meet appropriate academic quality and ethical standards
- There needs to be a system for rating the quality of journals so that ordinary doctors and researchers have some yardstick to guide them. At present there are too many poorly refereed Js and quality gets drowned out by quantity
- The quantity of publication needs to be diminished by de-emphasising the need to publish in order to achieve career progression in academia (itself partly a consequence of the free-market make universities pay philosophy)
- The refereeing system should be formalised and audited and the service of refereeing (and teaching etc) must be accorded similar status to research itself.
- To forbid members of medical colleges from participating in any activity outside that system, or from acting unethically in relation to scientific publications (e.g. ghost writing). Such action should be made the subject of disciplinary action by Medical boards etc.
- Give regulatory authorities more teeth in relation to drug approval and power to demand proper post-marketing surveillance where needed (which is currently virtually non-existent (68)).
Remember Horton concluded: “It is surprising and disappointing that this danger does not seem a serious priority within medicine itself.” Doctors have the power to change this overnight, but have they got the balls and the moral fortitude?
Drug companies might then be taught to walk to heal like well behaved dogs should (I love dogs, in their place).
Patient organizations, and individual patients (yes, every individual action and vote really does count), also have a similar monopoly and power to change things overnight: they can decline to participate in any trials unless they are carried out under those or similar satisfactory conditions. Patient advocacy groups really need to get together and call the shots; if they did that it would be game-over tomorrow.
Any of these actions would precipitate changes that would make an avalanche look small and slow.
For those who would like a deeper appreciation of the profoundly negative effect of American free market capitalism on medicine see my theme commentary on Science [link] and especially the two books by Oreskes & Michaels (69, 70).
Also, read Jeanne Lenzer on Whistle blowers from the pharmaceutical industry (71) and the NEJM paper (72).
She interviewed Kathleen Slattery-Moschkau, a former drug representative who wrote and directed the movie ‘Side Effects’.
- Light, DW, Basic research funds to discover important new drugs: Who contributes how much?, in Monitoring financial flows for health research:Behind the global numbers, MA Burke and A de Francisco, Editors. 2006, Global Fund for Health Research: Geneva. p. 29-43.
- Morgan, S, Grootendorst, P, Lexchin, J, Cunningham, C, et al., The cost of drug development: a systematic review. Health Policy,2011. 100(1): p. 4-17.
- Avorn, J, Teaching clinicians about drugs–50 years later, whose job is it? N. Engl. J. Med.,2011. 364(13): p. 1185-7.
- Gotzsche, PC, Hrobjartsson, A, Johansen, HK, Haahr, MT, et al., Ghost Authorship in Industry-Initiated Randomised Trials. PLoS Med,2007. 4(1): p. e19.
- Herxheimer, A, Memorandum by Professor Andrew Herxheimer (P165) Evidence to Select Committee. House of Commons Publications on the internet, Health Committee Publications, Health – Minutes of Evidence,2004: p. http://www.parliament.the-stationery-office.co.uk/pa/cm200405/cmselect/cmhealth/42/4101401.htm.
- Ghost writing initiated by commercial companies. J. Gen. Intern. Med.,2005. 20(6): p. 549.
- Pattison, N and Warren, L, 2002 Drug Industry Profits: Hefty Pharmaceutical Company Margins Dwarf Other Industries. Public Citizen Congress Watch,2003: p. www.citizen.org/documents/Pharma_Report.pdf.
- Huston, P, Reporting on surveys: information for authors and peer reviewers. CMAJ,1996. 154(11): p. 1695-704.
- Siontis, KC, Evangelou, E, and Ioannidis, JP, Magnitude of effects in clinical trials published in high-impact general medical journals. Int. J. Epidemiol.,2011. 40(5): p. 1280-91.
- Pereira, TV and Ioannidis, JP, Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects. J. Clin. Epidemiol.,2011. 64(10): p. 1060-9.
- Ioannidis, JP, An epidemic of false claims. Competition and conflicts of interest distort too many medical findings. Sci. Am.,2011. 304(6): p. 16.
- Lathyris, DN, Patsopoulos, NA, Salanti, G, and Ioannidis, JP, Industry sponsorship and selection of comparators in randomized clinical trials. Eur J Clin Invest,2010. 40(2): p. 172-82.
- Ioannidis, J, Lies, Damned Lies, and Medical Science. Atlantic,2010. November 17th.
- Kassirer, JP, Excerpts from: On the take. Physician Exec.,2005. 31(2): p. 28-32.
- Wazana, A, Physicians and the pharmaceutical industry: is a gift ever just a gift? JAMA,2000. 283(3): p. 373-80.
- Sheldon, T, GPs warned on accepting hospitality from drug companies. Br. Med. J.,2001. 322(7280): p. 194.
- Healy, D and Thase, ME, Is academic psychiatry for sale? Br J Psychiatry,2003. 182: p. 388-90.
- Sheldon, T, Drug company fined for excessive hospitality. Br. Med. J.,2001. 322(7283): p. 382.
- Weatherall, D, Academia and industry: increasingly uneasy bedfellows. Lancet,2000. 355(9215): p. 1574.
- Saidman, LJ, Drug company-supported symposia: what should be disclosed? Anesth. Analg.,2000. 91(2): p. 495-6.
- Norton, JW, Is academic medicine for sale? N. Engl. J. Med.,2000. 343(7): p. 508; discussion 510.
- Tramer, MR, Reynolds, DJ, Moore, RA, and McQuay, HJ, Impact of covert duplicate publication on meta-analysis: a case study. Br. Med. J.,1997. 315(7109): p. 635-40.
- Smith, RL, Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med,2005. 2: p. e138.
- Horton, R, The dawn of McScience. New York Rev Books,2004. 51: p. 7-9.
- Angell, M, The truth about drug companies: How they deceive us and what to do about it. New York: Random House,2005: p. 336.
- Ioannidis, JP, Why most published research findings are false. PLoS Med,2005. 2(8): p. e124.
- Papanikolaou, GN, Baltogianni, MS, Contopoulos-Ioannidis, DG, Haidich, AB, et al., Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions. BMC Med Res Methodol,2001. 1: p. 3.
- Als-Nielsen, B, Chen, W, Gluud, C, and Kjaergard, LL, Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA,2003. 290(7): p. 921-8.
- Chan, AW, Hrobjartsson, A, Haahr, MT, Gotzsche, PC, et al., Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA,2004. 291(20): p. 2457-65.
- Taylor, R and Giles, J, Cash interests taint drug advice. Nature,2005. 437(7062): p. 1070-1.
- Martinson, BC, Anderson, MS, and de Vries, R, Scientists behaving badly. Nature,2005. 435(7043): p. 737-8.
- Kirsch, I and Moore, TJ, The Emperor’s New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration. Prevention & Treatment,2002. 5: p.http://journals.apa.org/prevention/volume5/pre0050033r.html.
- Parker, G, Anderson, IM, and Haddad, P, Clinical trials of antidepressant medications are producing meaningless results. Br J Psychiatry,2003. 183: p. 102-4.
- Grimes, DA and Schulz, KF, Surrogate end points in clinical research: hazardous to your health. Obstet. Gynecol.,2005. 105(5 Pt 1): p. 1114-8.
- Gillman, PK, Fifty years of poor science. Br J Psychiatry,2003: p.http://bjp.rcpsych.org/cgi/eletters/183/2/102.
- Carter, BL, Blood pressure as a surrogate end point for hypertension. Ann Pharmacother,2002. 36(1): p. 87-92.
- Gotzsche, PC, Liberati, A, Torri, V, and Rossetti, L, Beware of surrogate outcome measures. Int. J. Technol. Assess. Health Care,1996. 12(2): p. 238-46.
- Carroll, BJ, Bringing back melancholia. Bipolar Disord,2012. 14(1): p. 1-5.
- Smith, D, Dempster, C, Glanville, J, Freemantle, N, et al., Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry,2002. 180: p. 396-404.
- Geddes, JR, Carney, SM, Davies, C, Furukawa, TA, et al., Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet,2003. 361(9358): p. 653-61.
- Angst, F, Stassen, HH, Clayton, PJ, and Angst, J, Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord,2002. 68(2-3): p. 167-81.
- Khan, A, Khan, S, Kolts, R, and Brown, WA, Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry,2003. 160(4): p. 790-2.
- Simon, GE, Savarino, J, Operskalski, B, and Wang, PS, Suicide risk during antidepressant treatment. Am J Psychiatry,2006. 163(1): p. 41-7.
- Harris, EC and Barraclough, B, Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry,1997. 170: p. 205-28.
- Tondo, L, Hennen, J, and Baldessarini, RJ, Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr. Scand.,2001. 104(3): p. 163-72.
- Moncrieff, J, Are antidepressants overrated? A review of methodological problems in antidepressant trials. J. Nerv. Ment. Dis.,2001. 189(5): p. 288-95.
- Solomon, DA, Leon, AC, Mueller, TI, Coryell, W, et al., Tachyphylaxis in unipolar major depressive disorder. J Clin Psychiatry,2005. 66(3): p. 283-90.
- Goodman, NW, Who will challenge evidence-based medicine? J. R. Coll. Physicians Lond.,1999. 33(3): p. 249-51.
- Bekelman, JE, Li, Y, and Gross, CP, Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA,2003. 289(4): p. 454-65.
- Gupta, RK, Tiller, JW, and Burrows, GD, Dual action antidepressants and some important considerations. Aust NZ J Psychiatry,2003. 37(2): p. 190-5.
- Millan, MJ, Gobert, A, Rivet, JM, Adhumeau-Auclair, A, et al., Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur. J. Neurosci.,2000. 12(3): p. 1079-95.
- Gillman, PK, A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Hum Psychopharmacol,2006. 21: p. 117-25.
- Shorter, E and Tyrer, P, Separation of anxiety and depressive disorders: blind alley in psychopharmacology and classification of disease. Br. Med. J.,2003. 327(7407): p. 158-60.
- Parker, GB, Commentary on diagnosing major depressive disorder: ask less that we embrace major depression and ask more what the concept does for us. J. Nerv. Ment. Dis.,2006. 194(3): p. 155-7.
- Parker, G, Roy, K, Wilhelm, K, and Mitchell, P, Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J Clin Psychiatry,2001. 62(2): p. 117-25.
- Parker, G, Roy, K, Hadzi-Pavlovic, D, Mitchell, P, et al., Subtyping depression by clinical features: the Australasian database. Acta Psychiatr. Scand.,2000. 101(1): p. 21-8.
- Parker, G, Classifying depression: should paradigms lost be regained? Am J Psychiatry,2000. 157(8): p. 1195-203.
- Wijkstra, J, Lijmer, J, Balk, FJ, Geddes, JR, et al., Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis. Br J Psychiatry,2006. 188: p. 410-415.
- Hirschfeld, RM, Montgomery, SA, Aguglia, E, Amore, M, et al., Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry,2002. 63(9): p. 826-37.
- Hale, AS, Procter, AW, and Bridges, PK, Clomipramine, tryptophan and lithium in combination for resistant endogenous depression: seven case studies. Br J Psychiatry,1987. 151: p. 213-7.
- Ashcroft, GW, Psychological medicine. Management of depression. Br. Med. J.,1975. 2(5967): p. 372-6.
- Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol,2011. 31(1): p. 66-74.
- Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol,2007. 151(6): p. 737-48.
- Gillman, PK, Pharmaceutical company influence. PLoS Med,2006. 2(12): p.http://www.plosmedicine.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F365dc4a0-abca-462d-8e43-55878582b369&root=info%3Adoi%2F10.1371%2Fannotation%2F365dc4a0-abca-462d-8e43-55878582b369.
- Gillman, PK, Disease mongering: one of the hidden consequences. PLoS Med,2006. 3(7): p. e316. DOI: 10.1371/journal.pmed.0030316.
- Sotelo, J, Regulation of Clinical Research Sponsored by Pharmaceutical Companies: A Proposal. PLoS Med,2006. 3(7): p. e306 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16805651
- Roehr, B, FDA should tighten post-marketing surveillance of prescription drugs, says Institute of Medicine. BMJ,2012. 344: p. e3104.
- Conway, EM and Oreskes, N, Merchants of Doubt: How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming. 2011: Bloomsbury Publishing.
- Michaels, D, Doubt is their product: how industry’s assault on science threatens your health. 2010.
- Lenzer, What Can We Learn from Medical Whistleblowers? PLoS Med,2005. 2: p. e209
- Kesselheim, AS, Studdert, DM, and Mello, MM, Whistle-blowers’ experiences in fraud litigation against pharmaceutical companies. N. Engl. J. Med.,2010. 362(19): p. 1832-9.
84. Steel, N, Abdelhamid, A, Stokes, T, Edwards, H, et al., A review of clinical practice guidelines found that they were often based on evidence of uncertain relevance to primary care patients. J. Clin. Epidemiol., 2014. 67(11): p. 1251-7.
85. Every‐Palmer, S and Howick, J, How evidence‐based medicine is failing due to biased trials and selective publication. J. Eval. Clin. Pract., 2014. 20(6): p. 908-914.
86. Popper, K, The Demarcation between Science and Metaphysics. Conjectures and Refutations: The Growth of Scientific Knowledge (1963), 1963. Ch 11.
87. Joiner, K and Lusch, R, Evolving to a new service-dominant logic for health care. Innovation and Entrepreneurship in Health, 2016.
88. Hoffmann, TC, Montori, VM, and Del Mar, C, The connection between evidence-based medicine and shared decision making. JAMA, 2014. 312(13): p. 1295-1296.
89. Moncrieff, J and Thomas, P, The pharmaceutical industry and disease mongering. Psychiatry should not accept so much commercial sponsorship. Br. Med. J., 2002. 325(7357): p. 216; author reply 216.
90. Moynihan, R, Heath, I, and Henry, D, Selling sickness: the pharmaceutical industry and disease mongering. Br. Med. J., 2002. 324(7342): p. 886-91.
91. Moynihan, R and Henry, D, The Fight against Disease Mongering: Generating Knowledge for Action. PLoS Med, 2006. 3(4): p. e191 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16597180.
92. Tiihonen, J, Tanskanen, A, Hoti, F, Vattulainen, P, et al., Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry, 2017. 4(7): p. 547-553.
93. Jones, H, Geddes, J, and Cipriani, A, Lithium and Suicide Prevention, in The Science and Practice of Lithium Therapy, G Malhi, JM Masson, and F Bellivier, Editors. 2017, Springer. p. 223-240.
94. Wingard, L, Boden, R, Brandt, L, Tiihonen, J, et al., Reducing the rehospitalization risk after a manic episode: A population based cohort study of lithium, valproate, olanzapine, quetiapine and aripiprazole in monotherapy and combinations. J Affect Disord, 2017. 217: p. 16-23.
95. Baldessarini, RJ and Tondo, L, International suicide rates versus adequate treatments. The British Journal of Psychiatry, 2017. 210(4): p. 298-299.
96. Shah, A, Bhat, R, Zarate-Escudero, S, DeLeo, D, et al., Suicide rates in five-year age-bands after the age of 60 years: the international landscape. Aging Ment Health, 2016. 20(2): p. 131-8.
97. Curtin, SC, Warner, M, and Hedegaard, H, Increase in Suicide in the United States, 1999-2014. NCHS Data Brief, 2016(241): p. 1-8.
98. Viola, S and Moncrieff, J, Claims for sickness and disability benefits owing to mental disorders in the UK: trends from 1995 to 2014. BJPsych Open, 2016. 2(1): p. 18-24.
99. Tiihonen, J, Lonnqvist, J, Wahlbeck, K, Klaukka, T, et al., 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet, 2009. 374(9690): p. 620-7.
100. Brown, J, Hanlon, P, Turok, I, Webster, D, et al., Mental health as a reason for claiming incapacity benefit—a comparison of national and local trends. Journal of public health, 2008. 31(1): p. 74-80.
101. Whitaker, R and Cosegrove, L, Psychiatry under the influence. 2015: Macmillan.
102. Gotzsche, PC, Young, AH, and Crace, J, Does long term use of psychiatric drugs cause more harm than good? BMJ, 2015. 350: p. h2435.