*A parody on Oscar Wilde [foxhunting: the unspeakable in pursuit of the uneatable]

*’Indefensible’, i.e., calling SSRIs antidepressants, when they are merely anxiolytics

A follow-on to Healy, “Do Randomized Controlled Trials Add to or Subtract from Clinical Knowledge?” and Beasley’s comment

https://inhn.org/controversies/david-healy-do-randomized-controlled-trials-add-to-or-subtract-from-clinical-knowledge.html

Introduction

Why SSRIs are not anti-depressants

That is an apt sub-title. 

As Trump has illustrated, if you tell lies loud enough and often enough, they drown the truth, which becomes forgotten.  Such is the situation with the acceptance of the unscientific belief that SSRIs are anti-depressant drugs.  Indeed, the term anti-depressant has become almost meaningless and reminds us of what Humpty Dumpty said:

Words mean what I want them to mean, nothing more and nothing less.

I am putting this modified and expanded version of my comment, that the INHN have published, on my website, because readers may find it interesting.  It is relevant because it reminds us that there are many other eminent thinkers who are also of the opinion that RCTs are over-rated and have got out of control.  They are neither as good, nor as useful, as they are cracked up to be.  Indeed, it is my opinion (and Healy’s) that they have done more harm than good over this last few decades — that is not just a provocative statement, it is a very serious statement with a great deal of evidence to support it, and immense consequences, which readers will find expanded on in various other commentaries that I have written.

It is a close parallel to what Trump has illustrated, which is, if a group comprehensively undermines truth and reason in a given field, then you can soon persuade many people that black is white.  Such comments would be incomplete without an allusion to George Orwell:

‘Political [scientific] language is designed to make lies sound truthful and murder respectable, and to give an appearance of solidity to pure wind.’ “Politics and the English Language”, 1946

RCTs are condemned by their own hand, insofar as they have played the most prominent role in falsely establishing SSRIs as ‘antidepressants’ when they are not — that is a stupendous feat of clinical misdirection.

RCTs have falsely positioned SSRIs as ‘antidepressants’

which is a stupendous feat of clinical misdirection

Below is my extended, amended, and emended website-version of my INHN contribution (see my YouTube video too).

The INHN debate and background

The discussion (on the INHN website) has become a peregrination of protracted prolixity — I do not suppose there will be Aprilany with the fortitude to digest Beasley’s 26,000 turgid words.  Therefore, I am adding, as briefly as possible, to my previous concise comment (on INHN).  The above alliteration of ‘Ps’ is a satirical reflection on the excessive, unscientific, and illogical reliance on P-values that pervades RCTs and has been railed against repeatedly by eminent statisticians for several decades, without much effect [1, 2].  Those two citations are but two of the dozens that could be given to support this point.

For those who do not already know, Professor Healy is an eminent writer and commentator on the history of psychiatry and especially the history of pharmaceutical company ‘activity’, and author of several books including the ingeniously titled best-seller Pharmageddon.

As a result of Healy’s extensive studies and access to otherwise unknown pharmaceutical company material resulting from his participation in various lawsuits, he advances the well-founded argument re SSRIs that:

[Their] anxiolytic, rather than depression profile, fits with the fact that SSRIs are ineffective for melancholia in all age groups. These drugs that are useless for “proper” depression became “antidepressants” in part to skirt clinical concerns that any new anxiolytic would necessarily produce dependence as the benzodiazepines had.

It is also noteworthy that the Nobel Prize winning pharmacologist Arvid Carlsson also agreed with this and called SSRIs serenics, not ADs.

Carlsson was awarded the Nobel Prize in Medicine in 2000 and was involved in the development of the first SRI drug called zimelidine (marketed in 1982), long before Prozac [3-5].  His opinion may therefore be considered as respected — more so than Beasley’s one might think.  Zimelidine was an analogue of chlorpheniramine and brompheniramine, antihistamines with SRI activity.

I agree with Professor Healy’s thesis about RCTs and have made similar points in my own writings.  Much evidence indicates that RCTs have subtracted from clinical knowledge, inhibited the progress of clinical knowledge, inhibited the development of research techniques, and especially inhibited adoption of best practice clinical management.

The history of the development of SSRIs and the deceitful marketing of them as ‘antidepressants’ rather than serenics or anxiolytics, is eloquent testimony to the misleading use of, and effect of, RCTs

I emphasise one simple fact about the recent definitive meta-analysis of ‘quality’ RCTs concerning antidepressants, the “Lancet 21 anti-depressant” study [6], about which I have written extensively elsewhere.  That analysis of many RCTs impels one major conclusion: that this enormous, mediocre quality, predominantly industry funded, RCT-work provides negligible useful information or guidance to doctors, especially specialists, and no useful information whatsoever about the real efficacy, mode of action, or pharmacology of the drugs concerned.  That is what real science must be about; not interminable comparisons of coloured jellybeans on the scores produced by some mediocre rating scale that does not even rate the core symptoms of the illness properly.  Such studies have shown that A>B>C>A, which I have dubbed previously, “Penrose stairs with drugs”.

RCTs show A>B>C>A, “Penrose stairs with drugs”

Who and what is Beasley?

Mr Charles Beasley ‘Junior’ was a long-term Eli Lilly employee — I doubt if it is meaningful to regard him as a ‘doctor’, since he does not appear to have practiced clinical medicine for decades, perhaps he is not a registered specialist either.  Almost all the citations incorporating his name are about either fluoxetine or olanzapine.  He would appear to be someone of limited scientific experience and of narrow and limited intellectual accomplishment.  Half of all the papers he has ever published have been about fluoxetine, and he has not published (in PubMed) any original single author papers in his whole life.  He certainly has no serious expertise in statistics (as he stated, under oath, in court); but he pontificates about them.

Those are not ad hominem comments, but observations on facts about his curriculum vitae, so that we can all have a better understanding of ‘where he is coming from’, as they say nowadays.

It is likely that most of the papers with his name attached to them were ghost written (almost all industry sponsored papers are ghost-written) — the companies that provide publication and writing services to industry have a turnover of hundreds of millions per year.

One is left to wonder exactly what his contribution might have been.  He, and his industry colleagues, have served to get many marginally useful ‘me-too’ drugs over the finishing line for FDA approval — that is not to the benefit of the patients, but is to the benefit employees, stockholders, and KOLs of pharmaceutical companies.

If he has the capacity for reflection about his achievements, in his retirement, he will be suffering from existential angst from which his excessive verbiage is probably an inadequate defence.

Usefulness of RCTs

Such meagre progress after 50 years — more than half a century — and it takes Beasley 26,000 words*, in his INHN response to Healy, to suggest what, yet still, needs to be done to improve it.  Well, he has had his chance.  If he and his associates could not ‘get it right’ after 50 years and devoting much of their careers to the enterprise, what chance have they got in future?  That tells us it is an unhelpful endeavour.  Is there a sound basis justifying a continuation of their efforts?  Have they suddenly found the route to success, despite these decades of failure?  What chance of progress with RCTs?  The 22^nd century?

*If I ever write 26,000 words in response to anyone’s article you would be justified in regarding me as a monomaniac and thinking I was getting things completely out of proportion, or that I had fallen off my trolley.

Beasley parades a preoccupation, obsession even, with what the famous mid-20^th century statistician, Hill, did or did not say or mean, nearly one century ago: things have moved on a since then.  For instance, with the work of the Turing prize-winner Judea Pearl, that I mentioned in my previous comment (INHN) and which Beasley does not even mention, and one presumes is completely unaware of.  Neither does he mention the improving appreciation, and use, of Bayesian reasoning, which in my opinion is an essential prelude to understanding the meaningfulness, or otherwise, of P values.

Incidentally, Hill’s report on illness in the cotton mills contained no statistics whatsoever; he said that double-blind trials and randomisation were only necessary if the differences were small.

Small, miniscule, non-existent: that covers pharmaceutical company RCTs of psychotropics.

Hill also made a point of endorsing Claude Bernard’s view that there is ‘no qualitative epistemic difference between experiment [RCTs] and observation’ [clinical science/experience].  How arrogant, uninformed, and presumptuous of Beasley and his ilk to implicitly demean the value of everyone’s clinical experience and experimentation with the dubious claim of ‘gold-standard’ status for RCTs.

RCTs are akin to fiddling with the fine-tuning knob when the radio-receiver is on the wrong waveband

Pearl said, “Science is nothing without causality” and RCTs contribute nothing to understanding causality — they are impotent in that regard.

Buried in Beasley’s turgid 26,000 words of text is the statement: “… RCT is the most robust method [gold-standard] for advancing sound clinical knowledge.” 

I profoundly disagree with that, as do many scientists.  Here are just a few significant references and comments about RCTs/EBM supporting that view:

Ashcroft [7] ‘autonomous of the basic sciences…blind to mechanisms of explanation and causation’

Solomon [8], ‘Emphasis on EBM has eclipsed other necessary research methods in medicine’

Berwick [9], ‘we have overshot the mark with EBM’;

Sir Michael Rawlins in his Harveian Oration [10] argued that: ‘the notion that evidence can be reliably placed in hierarchies [as all guidelines do] is illusory … Yet the technique has important limitations of which four are particularly troublesome: the null hypothesis, probability, generalisability, and resource implications.’

The meagre advances RCTs have contributed to clinical science and knowledge are an eloquent testimony to the validity of these assertions about the greatly overvalued and overemphasised role of RCTs.

The advances, of substance, in clinical practice and management, over the history of psychopharmacology, have come from clinical science and clinical observation, never from RCTs

Contrariwise, RCTs have undoubtedly led to much serious misinformation and misdirection which has done a great deal of harm to patient care and management.  Those who do not practice clinical medicine, like Beasley, will not have much appreciation of these life and death issues.  Beasley will not have been involved in patient care since he left medical training (after his residency) to join the pharmaceutical industry, so he has had no substantial practical experience or responsibility in clinical practice and management for several decades, if ever.

RCTs have done serious harm because they have influenced practice in the treatment of depressive illness such that doctors routinely give SSRIs to patients who have serious depression when there is no evidence that they work, which perpetuates people’s suffering and delays the usage of effective treatment

Finally, Beasley curiously says, “after I read past [sic] what I consider Dr. [sic]* Healy’s rather vitriolic descriptions of his concerns with RCTs…”. 

*I insert ‘sic’ above solely to highlight Beasley’s repeated use of ‘sic’ by which he draws gratuitous attention to what he considers are other’s [spelling] errors, by which he reveals both his own childish pedantry and his lack of knowledge of the history of English and spelling.  As various observers have commented, the repeated use of the term ‘sic’ is frequently a kind of linguistic snobbery, although it often back-fires on people, as it does in this case, because they do not understand as much about English as they think they do — I have often been amused by it, some referees ‘correct’ prose as if they were schoolmasters; well, failed schoolmasters.  Since Healy is a professor, Beasley could have afforded him the courtesy of using that title.  I expect his use of ‘Dr’ rather than ‘Professor’ was deliberate and as such is, again, puerile.

Beasley characterised Healy’s comments as “vitriolic” (OED “acrimonious, caustic, scathing”). 

One might observe that one can be vitriolic towards a person, but not towards an abstract entity (an RCT), so that tells us something about how Beasley is revealing his over-sensitivity of attitude and his Identification with, and fixation about, the RCT-concept.  Indeed, it is hardly surprising that he would say that: his whole professional life has been devoted to the RCT-cause.  But perhaps devoted is not the right word since it insinuates a degree of asceticism, which I doubt is the case, because I expect he has been handsomely rewarded for his work and that his shares in Eli Lilly alone are probably worth more than my entire pension fund.

Beasley’s characterisation of Healy’s comments as ‘vitriolic’ is quite out of proportion, unless he has a latent ‘super-sensitivity’ of conscience concerning his career in the pharmaceutical industry.  Has Healy has hit a tender spot? — after all, Beasley fails to mention the consistent and persistent lack of honesty and probity of an embarrassing proportion of the people with whom he ‘rubbed shoulders’ in his work.

I could make many justifiably vitriolic comments about how such widespread and persistent dishonest behaviour has wasted a great deal of my valuable time and intellectual energy in sifting through these deceitful and fraudulent publications in search of quality data, objectivity, and truth, e.g., [11, 12].  Those familiar with my work may already have read the several different commentaries I have written dissecting that sort of deceit in ‘tedious’ detail — it is tedious to detail, but if one is going to make these kinds of robust criticisms, one is obliged to adduce strong evidence to justify them, as I have done.

Lastly, it seems clear to me that Beasley has a less than impressive understanding of science, logic, methodology, and statistics; obsessional personality characteristics are strongly suggested by his writing-style; this may be what inhibits him from ‘seeing the forest for the trees’ — that is a common characteristic of people with obsessional traits, they become fixated on one line of thought and have difficulty changing track.  He may be one of the people who would benefit from Prozac, since obsessionality is one thing it can be useful for.

References

1. Levine, T.R., et al., A critical assessment of null hypothesis significance testing in quantitative communication research. Human Communication Research, 2008. 34(2): p. 171-187.
2. Greenland, S., et al., Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol, 2016. 31(4): p. 337-50.
3. Peterson, I. and R. Wllley, Zimelidine: a new antidepressive. Br J DIs Chest, 1975. 69: p. 267-72.
4. Lindberg, U.H., et al., Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols. J Med Chem, 1978. 21(5): p. 448-56.
5. Lindberg, U.H., et al., Inhibitors of neuronal monoamine uptake. I. Selective inhibition of 5-hydroxytryptamine uptake by alpha-aminoacid amides of phenethylamines. Acta Pharm Suec, 1978. 15(2): p. 87-96.
6. Cipriani, A., T.A. Furukawa, and G. Salanti, Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 2018. 391(10128): p. 1357–1366 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext.
7. Ashcroft, R.E., Current epistemological problems in evidence based medicine. J Med Ethics, 2004. 30(2): p. 131-5.
8. Solomon, M., Just a paradigm: evidence-based medicine in epistemological context. European Journal for Philosophy of Science, 2011. 1(3): p. 451.
9. Berwick, D.M., Broadening the view of evidence-based medicine. Qual Saf Health Care, 2005. 14(5): p. 315-6.
10. Rawlins, M., De testimonio: on the evidence for decisions about the use of therapeutic interventions. Lancet, 2008. 372(9656): p. 2152-61.
11. Gillman, P.K., Drug interactions and fluoxetine: a commentary from a clinician’s perspective. Ex Op Drug Saf, 2005. 4: p. 965-969.
12. Gillman, P.K., A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Human Psychopharmacology. Clinical and Experimental, 2006. 21(2): p. 117-25.