Why Most New Antidepressants Are Ineffective: And How Pharmaceutical Companies Have Deceived Doctors

[Guest guest]

[This author is a highly respected, heavily published medical

doctor/professor/researcher who has been widely published since the 1970's.

He does not accept any money, gifts, or contracts from drug companies. He

very much believes in the medical model. Despite his background and

beliefs, he wrote this article charging that the pharmaceutical industry is

corrupt, lies about their drugs, and has provided very few drugs of any use

in depression. He also calls physicians and medical journals to task for

colluding on this deceit. Please don't hesitate to print this out and give

it to your physician(s) and other hoodwinked medical professionals, and pass

it out to friends and family. Send a copy to your legislators, please.

There are numerous websites now providing email addresses for all

representatives.--]

Why Most New Antidepressants Are Ineffective: And How Pharmaceutical

Companies Have Deceived Doctors

by Dr. Ken Gillman MRC Psych (Australia)

I am a lifelong pharmacologist, my professional life as a 'psychiatrist' (I

actually prefer to be called a clinical neuropharmacologist) has been spent

treating depressive illnesses that require drugs. I have published a number

of original papers on psychopharmacology in the most 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 the current generation of

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. Most

people who read this can help to change things, so read on, and I will

suggest 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. The Lancet editor, 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:

http://www.parliament.the-stationery-office.co.uk/pa/cm200405/cmselect/cmhealth/\

42/4121604.htm

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

Herxheimer (1) 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

(GlaxoKline). 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, 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 (2) , '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:--

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=1598733\

3

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 (3)

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

http://www.wanttoknow.info/truthaboutdrugcompanies 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 even deceit

(4). 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. 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 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' (5). 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 (6) , so it works. A growing number of

observers are feeling uneasy about the proportion of doctors who fit this

mould (7-12). 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 (4,13), 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. usually 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

, are not paranoid conspiracy theorists, but long-time pillars

of the medical establishment. , editor of the BMJ for 25 years, wrote

that 'Medical Journals Are an Extension of the Marketing Arm of

Pharmaceutical Companies' (14). Horton, of the Lancet, stated, 'Journals

have devolved into information laundering operations for the pharmaceutical

industry' (15), and Angell an NEJM editor said pharmaceutical companies

were, 'primarily a marketing machine . co-opting every institution that

might stand in its way' (16) . 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 (4, 13,17): 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 (1, 18-22).

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 (23): 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).

http://www.breggin.com/courtfiling.pbreggin.2006.html

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 (24). 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 science, and depression and its assessment.

Depression is difficult both to define and to measure, and the assessments

used are highly 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 (25-28). 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.

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 (29, 30). 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 (31). 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 (32, 33). 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%) (34,35). 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

(36), and no long term influence on the important outcome of suicide (33).

Of the patients who respond to initial treatment a significant proportion

subsequently relapse, despite continued high dose treatment (37).

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 (38).

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, '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 (29).

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' (39).

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 (40) has been clearly demonstrated to be based on unreliable and

unreplicated evidence, both in animal work (41), and human trials (42).

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 (43). 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, 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

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, ssen, 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 (24, 44-47). 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 (especially clomipramine) and MAOIs

and ECT are very probably more effective for these severe illnesses (48). 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 the most 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

(49); 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 (50, 51), 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 only helpful when

added to non-serotonergic drugs, because its most likely contribution is

that of a weakly serotonergic action. 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.

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.

Is there anything you and I can do to change the situation?

Yes. It is simple. Circulate this essay and the link to it (with appropriate

attribution please) and these very simple recommendations.

Science must be one step removed from influences concerning funding, and

from sales and advertising. This could be achieved through simple action

both by doctors, and by those 'patients' taking medications and

participating in drug trials.

Doctors could use their great (indeed monopolistic) power to promote (or

even enforce) actions like:--

a.. to cause to be set up independent research bodies that appoint

appropriately qualified experts to design and conduct drug trials (52, 53),

b.. to forbid members of specialist medical colleges from participating in

any activity outside that system, or from acting unethically in relation to

scientific publications. Such action could be made the subject of

disciplinary action by the General Medical Council (GMC), Medical boards

etc.

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.

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.

I suspect either of those actions would precipitate changes that would make

a class 5 snow avalanche look small and slow.

PS

Also, read Jeanne Lenzer on Whistle blowers from the pharmaceutical industry

(54). She interviewed Kathleen Slattery-Moschkau, a former drug

representative who wrote and directed the movie 'Side Effects'.

http://medicine.plosjournals.org/perlserv/?request=get-document & doi=10.1371/jour\

nal.pmed.0020209

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