Professor Gillman?

The ‘H-index’ average for Professors in medicine is approximately 15 (1). Mine is 22.

I have become more aware of the extent to which doctors have difficulty in assessing the reliability and value of scientific information on the Internet, or in scientific journals, or my status and reputation. The doctors who contact me for advice are often unaware of my many scientific publications (almost all sole-author papers: not, like many professors, multi-author papers, to which they may have contributed modestly).

When Doctors are presented with information they are frequently not able to critically asses the accuracy and authority of that information. They are often unaware that I have published many widely referenced review papers in reputable ‘first-division’ scientific journals, or that I am acknowledged as a leading world expert in serotonin toxicity, and other drug interactions. Aside from a few well-known journals like the BMJ, Lancet and NEJM, most doctors have little idea if a journal is a reputable ‘first-division’ journal, or just one of the myriad of 3rd-rate ‘Mickey-mouse’ journals (there are about 5,500 different journals in ‘Medline’ database!)

One can take the view that this is understandable and excusable, because Doctors are bombarded with so much rubbish that they have become jaded, and tend to assume this is just another bit of rubbish. So, it is important to help them to understand more.

I will contextualise my publications concisely. One of the main menus at the top is ‘Publications’, these are largely papers published in prestigious peer-reviewed scientific journals.

The link here, and on my homepage, to my ‘Google scholar’ profile is the simplest way to authenticate publication metrics. Google scholar provides detailed publication metrics: mine are superior to those of most academics at major ‘Ivy League’ and ‘Oxbridge’ universities. In brief, the typical ‘H-index’ for Professors in medicine is around 15. My H-index 22 (higher is, of course, better).

As far as individual publications are concerned, my Google scholar profile shows that some of my major review papers have been cited frequently (like > 300 times, which puts them in the top 0.1% of all papers) ***, and more frequently than any other comparable paper in the field. Indeed, some of them are now standard references in benchmark textbooks.

People frequently address me as Professor: that is appropriate, because although I do not hold a formal professorship, honorary or otherwise, at any university any more, I have more publications and more citations than most full professors.

As such, the quality and authority of the information in my review papers overrides recommendations in most standard texts and guidelines, such as those produced by the ‘National Institute of clinical excellence (in the UK), the ‘Maudsley therapeutic guidelines’ ***, the ‘physician's desk reference’ (USA equivalent of MIMs) and MIMs (the latter two being very poor sources of information – they are essentially defensive legal texts, not clinical pharmacology texts – yet MIMs and the PDR are widely used and on most doctors’ desks). Most textbooks in my fields of expertise are a couple of decades behind in terms of current best opinion and practice.

*** The Professor of pharmacy/pharmacology at the Maudsley, David Taylor, is the ‘lead author’ behind the Maudsley guidelines and a co-author of an appalling paper about serotonin toxicity, that I have criticised harshly, and deservedly. Because he has shown himself capable of putting his name to such disgracefully poor material, it is problematic for any cautious judge to put much confidence in his perspicacity for producing guidelines.

If a doctor with whom you are dealing cannot acknowledge such realities and learn the need to go beyond the PDR and ‘guidelines’ (which set are they using? there are many different and sometimes contradictory ones!), then the only advice I can offer is to remind them they are there to advise, not to dictate, find an alternative medical adviser, or complain via the available channels and procedures. If needed you should be accompanied to consultations by a mature family member or supporter who is capable of being assertive and persistent and demanding a second opinion which can often be obtained from the area ‘teaching’ or ‘university’ hospital.

It is crucial to highlight and repeat that guidelines are, and can only ever be, suggestions, and that they are only applicable to ‘typical’ cases (and few cases are really ‘typical’!): all good guidelines state that principle clearly in the preamble (which few people appear to read), and also emphasise that it is the doctors’ responsibility to asses each case individually, and not just apply guidelines in a rote fashion: indeed, to apply guidelines in a rote fashion may itself constitute negligence.

The fact that following guidelines may itself constitute negligence is ironic, since a frequent consideration and influence, when doctors are looking up guidelines, is to avoid criticism and censure, and also avoid the effort and hassle of thinking things through themselves, learning about ‘less-standard’ treatments. But, that is precisely what ‘professionals’, ‘specialists’, and ‘experts’ are paid high fees to do! But it appears that many find it much easier just to follow the guidelines.

*** One of the insidiously negative aspects of the ubiquitous problem of poor refereeing is, for example, that my ST review papers (and many other good review papers) should, in a properly functioning system, have been cited much more frequently. Poor refereeing is producing a kind of ‘regression to the mean’ in publishing metrics, because referees are not ensuring that appropriate benchmark references are cited when they should be. So, good work is under-cited and poor papers are over-cited. This results in a self-fulfilling promotion of mediocrity: a little dispiriting. So, my ‘H-index’ should be much higher, like 40 rather than 22.

References

1.         Doja, A, Eady, K, Horsley, T, Bould, MD, et al., The h-index in medical education: an analysis of medical education journal editorial boards. BMC Med Educ, 2014. 14: p. 251.

https://www.ncbi.nlm.nih.gov/pubmed/25429724

Small private sale of Persian carpets

Family circumstances dictate that a proportion of a modest collection of Persian carpets needs to be passed on to new owners.

Some of these carpets will stay in the family, but a proportion need to be sold to finalise family affairs.

The collection consists of a variety of town and tribal pieces, both ‘antique’ and new, some modest, like poshties worth just $100 or so, to small tribal carpets worth only a few hundred, and some larger finer examples. All are in excellent condition, clean and unmarked.

The collection needs to be sorted out by the end of 2017, so the best offer by that date will be the new owner.

For anyone who doesn't know much about Persian carpets it's worth knowing that their value is lower now than it has been for quite some time and it really is easy to pick up delightful pieces for modest price (like cheaper than a quality new machine made commercial carpet - it’s a topsy-turvy world). Anyone who's bought things like this for an ‘investment’, rather than because they love them – easy to do, is in for a severe disappointment of GFC-dwarfing proportions. So now is a good time to be adventurous.

I will post some pictures when I get organised, but if you are interested, get in early and contact me directly through the website giving me an indication of what size pieces you might want to consider so I can send some photographs. Sizes range from ‘posties’ of 100 x 80 cms, small rugs of 160 x 120 and some ‘carpets of 300 x 200 (e.g. a 70 raj Tabriz of 310 x 205).

This commentary incorporates suggestions for combatting the tidal waves of bad and dishonest science, flooding over us all via the medical journals that we read. Quite a long time ago I wrote about the dishonest practices and bad science in the field of atypical antipsychotic drugs, which have been a multi-billion-dollar source of income for big pharma for a couple of decades now. The original piece that I posted on this website about ‘Antipsychotics and Humpty Dumpty’ was republished in the Carlat psychiatry report in an abbreviated form, sometime later (1).

In that article I made passing reference to risperidone and the chicanery that had been engaged in to make it appear good (Huston et al.), better than haloperidol — which was of course going out of patent — and better than the other competing ‘newer’ drugs.

In the process of researching that commentary I contacted the Prof Leucht (2), who had written the meta-analysis relating to the relative merits of various of these drugs, including risperidone. I was enquiring of him why they had not referenced and discussed the paper ‘Redundancy, disaggregation, and the integrity of medical research’, by Huston et al. (3)*** when discussing the possibility of bias, fraud, and unpublished studies etc. His answer was that they were simply not aware of it. I do not suppose they searched the scientific data using words like fraud, dishonesty, etc. Many doctors are insufficiently ‘street-wise’ and insufficiently sceptical, or cynical. See also (4).

*** The title is a science-journal-acceptable way of saying ‘lying and cheating’.

That is an example of how even carefully done meta-analysis is often seriously flawed without anyone noticing it (except me, it seems). A sort of ‘whoops, we did not know the castle was built on sand’ moment.

I have done quite a lot of writing about bad science and fraud in science (see main menu ‘Bias in science’), but no amount of writing about it is going to change anything unless people decide enough is enough and take actions.

There are so many quotes and references one could give on this subject that it is difficult to choose: I will offer you the words of the retiring British medical journal editor of some years, Richard Smith (5, 6), that ‘Journals have devolved into information laundering operations for the pharmaceutical industry’: but see also my other commentaries on bad science, especially ‘Why Most New Antidepressants Are Ineffective: And How Pharmaceutical Companies Have Deceived Doctors’.

Part of Smith’s writing is a sort of mea culpa about why it took him so long to realize he was being duped as editor of a top medical journal. I will record the fact that I wrote to him, in response to something in the BMJ, a while before he resigned, to tell him I thought he was being duped. I like to think I may have played a small part in his ‘conversion’.

So, I wonder if this series of articles about risperidone (Risperdal™) in the ‘Huffington Post’ will precipitate anything useful? other than spreading the appreciation of the negative aspects of naked capitalism. Capitalism caught in flagrante delicto, as it were.

http://highline.huffingtonpost.com/miracleindustry/americas-most-admired-lawbreaker/

The big picture: information generation and dissemination

The misleading drug trials that permit big pharma to get their drugs approved are possible mainly because big pharma often has control of all the data from clinical trials (doctors have very naively allowed them to gain that control), that is but the tip of the ice-berg. Big pharma exerts considerable control over post-graduate medical education, medical journals, and the whole environment of information that doctors are exposed to on a day-to-day basis. Furthermore, big pharma has gained a strong influence over, or even control of, much of the process of legislation about drug licensing, the FDA, the formation of clinical guidelines, and more.

What are the ‘nutrients’ that have nourished this mutant growth of big pharma control?

The first essential element is getting the data. Patients, who all sign consent forms agreeing to participate in drug trials, and doctors who 'allow' them to do that, are giving big pharma control 'on a plate'. It is like putting the fox in charge of the hen-house. Anyone wishing to understand that a bit more just needs to look at the Huston review (3). If they have possession of the raw data (possession is nine-tenths of the law) they can manipulate it free from control and scrutiny — and we know, beyond any conceivable doubt, they do that ruthlessly and repeatedly (see Huston), despite multi-million dollar penalties for infringements. When one is raking in billions (not millions), that is just a minor cost of doing business.

Trials cannot be carried out without the essential raw material of patients! If patients only signed ‘consent’ forms that stipulated that the raw data must be held and controlled by to an independent party, that would be the beginning of the end of the story — a knockout blow. TKO in the first round, as they say.

There are various other somewhat similar measures that could be enacted as well, perhaps another key one would be to do with the metrics of ‘success’ used to assess researchers, and which determine their chances of progress and promotion. At present the system encourages poor research, multiple small publications (salami publishing) and puts so much pressure on most, that good people do less reviewing for journals. The huge proliferation of published journal titles means that more and more less expert people are acting as ‘referees/reviewers’ and the quality of published work is declining. In my area, much of what is published is simply rubbish. The proliferation of poorer quality material makes the finding of the better stuff more and more difficult, especially now that less researchers utilize the services of independent professional librarians (Journal cost to libraries have become so great that many places can no longer afford a librarian).

So, what goes naturally, hand-in-hand with the above, is a system for ‘rating’ (post-publication), the quality and value of material. That is quite straightforward if you think about what Google have achieved with search engines and advertisements. Such a system would link in to weighing the ‘publication’ metrics of authors in a way that would enable appointments committees and funding agencies to improve their decision making.

The proliferation of 3rd rate publications makes it harder and harder to figure out who is doing good work, and easier for big pharma to artificially elevate the apparent excellence of their chosen, groomed, candidates and place them in prestigious and influential positions (there are various ways they can do that, the bottom line is ‘money talks’). There is little reliable data on this, but I am sure it is much more widespread and consequential than most doctors appreciate. This proliferation of 3rd rate publications*** also makes it hard for ‘ordinary’ doctors, who may not have the ability to accurately deduce the quality of their source, to know what to trust and rely on when they wish to inform themselves with quality information. After I retired from clinical work and began publishing and writing much more, especially about bad and fraudulent science, I went through a period of being angry. I was angry because these dishonest people had caused me to waste so much of my intellectual effort wading through lies and rubbish to reach something approaching good and true science. I could have achieved so much more if I had not so frequently been lied to and conned.

*** There has been a burgeoning of the number of journals devoted to publishing case reports (from < 10 on 2005 to nearly 200 in 2016 (7).

Therefore, any measures that facilitate the better quality science getting a more prominent exposure to doctors will do a lot of good. The IT technology to achieve this already exists and could be applied tomorrow. Let me outline an illustration of this. An algorithm like the ones used in search engines, and to decide on the adverts you are shown, could give a score to published papers weighed by factors like: how long people have spent reading the material, what their professional and publication ranking in the field is, what score they give it on a scale (a more sophisticated version of ‘like’ feature), etc. Not exactly rocket science. So, if I spend a long time reading a paper on ST (as a world expert in that field) that should have a much bigger influence on its’ rating than if a nurse-practitioner from Woop Woop gives it a five-star rating. Such a system does not involve any kind of suppression of ‘non-mainstream’ ideas or any ‘censorship’, it just enhances people’s ability to know what has rated as good science by those more expert.

Big pharma is the predominant influence over clinical drug trials. Those who control clinical trials also control clinical guidelines, and clinical practice and most importantly, healthcare expenditure on drugs. They also strongly influence the general emphasis of healthcare spending. That pretty much covers all bases!

By, ‘the general emphasis of healthcare spending’ I mean, for instance, allocating money to anti-depressants drugs, rather than social and psychological services for the huge numbers of people classified as having ‘depressive illness’. Or, cardiac drugs, rather than sending people to the gym and teaching them to eat healthily.

Another thing many people would not even dream was happening is big pharma’s influence over classification of illness via DSM. That much expands their market.

I could go on: but, the point is that a lion’s share of the problem starts with patients giving-up their data unconditionally, which has allowed big pharma to high-jack the whole process, with very profitable results.

Doctors have acted as pathetic, wimpish bystanders and I am ashamed to call myself a doctor (well, I don’t, I am a clinical neuro-pharmacologist!).

Gillman’s solution

The first step in the campaign to correct this awful & crazy situation is to retain control of the data! This would require some sort of umbrella patient-trials organisation to protect and represent patients, who could supervise the 'data-collection/protection' process.

It would be simple to form an independent board of non-pharma research scientists, and other representatives (e.g. community, law etc.), to hold all the 'raw' trial data, and provide it to any bona fide researcher to analyse. There are many other similar changes that could be made — but the above is the first essential step.

That idea requires no new laws, no government intervention (although that could help), just the concerted action of individuals. Stop agreeing to participate in clinical trials (stop giving money to the church): things will change very quickly. If patient advocacy and support organizations pick up that baton, and run with it there would be trembling hands, pale faces, and hyper-active descending colons, in big pharma boardrooms over-night.

The message: 'if patients give their data away unconditionally, they are asking to be screwed, and they have been screwed, and they will continue to be screwed'. Just like people who give money to, or support, the Catholic church (except in that case they are asking for their children to be screwed).

Perhaps I will talk another time about what academia could do, along the same lines, to change the way papers are assessed, and academic promotion regulated. But I am afraid there are many wimps in that camp, so someone may have to put a bomb under them. And indeed, the bomb is the above. If they do not implement such changes then they could be ‘black-listed’ from participating in clinical trials. Patients could achieve that change without any help from laws, government or anyone else.

You have the power, if you wish to use it.

Sadly, my colleagues in the medical profession are somewhat naive and/or lacking in moral fortitude. Or are they just greedily taking big pharma money (If you think I am exaggerating, there is a web site that tells you how many $$$$$ your doctor has got from big pharma (for giving ‘education talks’ to nurses, para-medical staff of all sorts, and even their colleagues).

And we wonder why doctors have not been leaders in dealing with these crucial ethical and scientific issues.

Enough said.

PS. The dogma of RCTs as a gold standard

The dogma of RCTs as the gold standard has contributed greatly to the present situation in which those who control trials control clinical practice, via ‘clinical guidelines’, and aided by the pseudo-science of ‘meta-analysis’, which I now call the phrenology of the third millenium.

Healy D, Cattell D. Interface between authorship, industry and science in the domain of therapeutics. British Journal of Psychiatry (2003) 183: 22-27 & Charlton BG. Conflicts of interest in medical science: peer usage, peer review and 'CoI consultancy?' (editorial). Medical Hypotheses. 2004; 63: 181-186.

References

1.         Gillman, PK, Atypical antipsychotics: where is the science, where is the evidence. The Carlat Psychiatry Report, 2013. 11(1): p. 3-5.

http://pro.psychcentral.com/atypical-antipsychotics-where-is-the-science-where-is-the-evidence/006014.html

2.         Leucht, S, Kissling, W, and Davis, JM, Second-generation antipsychotics for schizophrenia: can we resolve the conflict? Psychol Med, 2009. 39(10): p. 1591-602.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19335931

3.         Huston, P and Moher, D, Redundancy, disaggregation, and the integrity of medical research. Lancet, 1996. 347(9007): p. 1024-6.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8606568

4.         McLaren, N, Psychiatry as Bullshit. Ethical Human Psychology and Psychiatry, 2016. 18(1): p. 48-57 http://theaimn.com/psychiatry-as-bullshit/.

5.         Smith, RL, Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med, 2005. 2: p. e138.

http://www.plosmedicine.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020138

6.         Smith, R, Travelling but never arriving: reflections of a retiring editor. Br. Med. J., 2004. 329(7460): p. 242-244.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15284125

7.         Akers, KG, New journals for publishing medical case reports. Journal of the Medical Library Association: JMLA, 2016. 104(2): p. 146 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816468/.

Introduction

Doctors have been prescribing this incredible drug more and more as they believe it to be of use in such a wide variety of conditions. It was first approved for schizophrenia (and therefore called an ‘anti-psychotic’) but then it seemed helpful in cases of depression, of all kinds, so is also regarded by many as a ‘mood stabiliser’ and anti-depressant and anti-manic agent. More recently still, it has been used in generalised anxiety disorder and sleep disturbance (and who does not suffer from those?), also for disturbed behaviour in old people, especially those in nursing homes: there are so many of them and they can be so ‘time-intensive’ and they will keep trying to get up out of their chairs (so much better if they just sleep their time away). We must not forget the little ones, what about ADHD, or whatever they have that is making them a pest. Yes, quetiapine may be the answer. And, there is more: it is finding a use in PTSD, anorexia nervosa, OCD, borderline personality disorder: indeed, there is an argument for just putting in the water supply.

The pharmaceutical company continue to be pleased with the sales, which I believe are now getting close to $100 billion; if only that pesky patent law could be altered, surely someone can come up Trump(s) on this one! that would be a Tr(i)ump(h). He might oblige.

I hope and trust no-one has read this far without realising that I am employing humour and sarcasm, because if I did not I would be so enraged about the whole obscene farce surrounding quetiapine that you would have been reading a tirade of abuse against the drug company, my gullible colleagues, and all the people involved in publishing the third-rate so-called ‘scientific papers’ about this drug.

No surprise; I am about to expound on just how bad and how dishonest it all is.

Who remembers ‘Flanders and Swan’? Even the young ones may have heard the ‘Hippopotamus’ song ‘Mud, mud, glorious mud’: in this context, I am reminded more of their witty song about the newly discovered multi-purpose vegetable called the ‘Wompom’, which provides everything imaginable

‘… the flesh in the heart of a wompom has the flavour of porterhouse steak,

and the juice is a liquor that will get you higher quicker,

and you’ll still get up next morning when you wake.

Take a break and listen, and if you get angry about the stuff below, listen again, it will bring a smile back.

https://www.youtube.com/watch?v=CsaNgsoQcO4

I choose the words ‘incredible’ and ‘believe’ in my first sentence because, as the old saying goes ‘If it sounds too good to be true, it is too good to be true’. Science is about replicated evidence, not belief, or impressions created by promotion and spin doctors. Doctors are especially susceptible to spin precisely because they think it affects others, but not them.

Unbelievable claims: ‘post-truth’ era science

There is neither good evidence that quetiapine has any useful pharmacological effect other than increased appetite, weight gain and sedation, nor that its’ hundredfold price differential over other available drugs (e.g. promazine or doxepin) is justified. These effects result from its’ most potent pharmacological property, by far, H1 antagonism. In other words, it is good for hay-fever! (see table).

Quetiapine’s potency is about 100 times greater at H1 vs D2 receptors: if it was marketed on the same basis as the SSRIs it might called a super-selective histamine blocker (SSHB)! I have been surprised while doing this update of quetiapine that none of the papers I have reviewed even mention, never mind discuss, its H1 potency: we certainly are living in the ‘post-truth’ era!

Here is the seminal paper linking weight gain and H1 potency from Solomon Snyder’s lab (1), and others (2-4). If you are a psychiatrist, and you do not know who Snyder is then you should be ashamed of yourself https://en.wikipedia.org/wiki/Solomon_H._Snyder

There is no evidence or reason for supposing quetiapine possesses useful or unknown new properties (see ‘fast-off’ below). Indeed, from a pharmacological point of view this drug regresses us to the dawn of psychopharmacology in the 1940s (see table below).

It is the first drug in the modern era to be prescribed widely for sleep, anxiety, depression and schizophrenia: it is either a miracle, or the most stupendous con-job ever perpetrated on patients, and the eternally gullible psychiatric fraternity.

Part of the reason the link between weight gain and psychotropic drugs (many have H1 potency) was slow to be recognised was that very few doctors bothered to weigh people, and if they did they never used properly calibrated accurate scales: I always weighed patients at every visit (on proper accurate scales) and it was obvious with the old TCAs that those with higher H1 potency caused more weight gain, like-wise with the anti-psychotics. I remember writing something about this around twenty years ago — I was astonished to find that most of the papers relied on patient self-reports of weight gain! That gives a vivid insight into how hopelessly unscientific most psychiatrists are — I wanted to shout at them, ‘haven’t you got a f**king set of scales’! One fellow took my breath away when he replied that proper scientific scales were too expensive.

Mutton dressed as lamb

A brief explanation may help. Many papers on the history of psycho-pharmacology relate how the tricyclic nucleus of the aniline dye, methylene blue, led to the discovery — France, the 1940s — of the first antipsychotic drug, chlorpromazine, and its’ structural analogues, the first tricyclic antidepressant (imipramine), and the first generation of antihistamines, promethazine (good old ‘Phenergan’). All these ‘tricyclic’ drugs are still on the market, including the ‘proto-typical’ promazine.

Promazine was regarded as too weak to be useful, and as is obvious from the names, led to the development of chlor-promazine (Largactil), the first antipsychotic drug. Adding electro-negative elements such as chlorine increases the potency of many tricyclics — hence, add chlorine, and imipramine becomes the much more potent ‘chlor-imipramine’, viz. clomipramine (Anafranil).

The table below gives the well-replicated pharmacological data demonstrating clearly that quetiapine is no different to promazine; on the face of it, we have returned to the 1940s.

Some drug, some progress.

Remember Winston? ‘Some chicken, some neck’. Ottawa 1942

https://www.youtube.com/watch?v=y6JxSHmVB5g

Table of Affinities (Ki nM)        

  D2 5-HT2A H1
Promethazine   250 170 1
Promazine       200 15 2
Chlorpromazine                   2 5 2
Quetiapine        500 150 7
Doxepin 350 25 0.2

Data from the PDSP database (approximate means from several sources, not all HCR data). https://kidbdev.med.unc.edu/databases/pdsp.php

Most drugs seem to need low single figure affinity potency (i.e. <10 nM) to produce clinical effects. An affinity of 500 nM is regarded as insignificant.

Note: For structure and 3D configuration See http://www.drugbank.ca/

What does it all mean?

What does it all mean? Much could be written about this; however, the rule of parsimony suggests that the simplest explanation is likely to be correct: the simplest explanation is that since there is so little pharmacological difference between promazine and quetiapine the likelihood of there being any substantial difference in their therapeutic efficacy in schizophrenia, or anything else, is small. I would say close to zero.

The same must be said of quetiapine’s supposed benefits for treating, or augmenting, depression. In that context, there is no basis for supposing it to be superior to doxepin, which is a useless anti-depressant, but the most potent anti-allergy drug on the world market — still, after 50 years!

The potencies in the table mean that for quetiapine we would expect no substantial effect in humans, other than H1 antagonism (viz. increased appetite, sedation), unless it is used in doses of around 1,000 mg daily, close to its toxicity threshold (the max recommended doses are between 300 – 800 mg, depending on indication).

A quick lesson from history

Incidentally, I have put doxepin in the table because it is similar and contains historical precedents and lessons. It was of course originally classified as a tricyclic antidepressant, despite its’ noradrenaline reuptake inhibitor potency being so weak as to be of no consequence whatsoever. It is one of the most potent antihistamines known, about equipotent to mirtazapine. That property (H1 antagonism) inevitably makes it increase appetite (promoting weight gain) and produce sedation, sleepiness and reduction of anxiety. Hence, over the decades, it has been used as a hypnotic and anxiolytic: indeed, around the time of my TCA review paper, which expounded on the usefulness of doxepin, ((5), see table 5), it was reformulated and marketed as a hypnotic in the USA (Silenor). There are dozens of similar drugs with antihistamine activity that have been used for appetite stimulation and sleep, as well as allergies, over the last 50 years (diphenhydramine, doxylamine, cyproheptadine, trimipramine, hydroxazine, promazine, promethazine, carbinoxamine, dimenhydrinate etc.).

For many years (mis-guided) psychiatrists used doxepin as an antidepressant, and some may still think it works: its most prominent clinical effect was of course sleepiness and weight gain which is inevitable because of its extremely potent H1 antagonism. It was useless as an antidepressant, except that it improved appetite, sleep and anxiety symptoms. That produces substantial improvements in depression the rating scales (see below) used to assess depression and hence allows it to be ‘misclassified’ as an antidepressant, even though it does not improve the core symptoms of anergia and anhedonia. This paragraph could be repeated with quetiapine (or mirtazapine) substituted for doxepin. It took psychiatrists 30 or more years to realise doxepin was useless, I don't suppose they will become enlightened about quetiapine any more quickly, since there is no reason to suppose the present generation are any smarter than the previous one. Indeed, they probably suffer from the disadvantage that they are even more influenced and indoctrinated by drug company ‘education’ and promotional material than previous generations.

Is there an explanation?

It is certainly possible to produce all sorts of far-fetched pharmacological theories that might account for a possible different in effect of Promazine and Quetiapine, even though current assay techniques indicate they are so similar. However, to be convincing such evidence would have to be reliably replicated by different research groups and a plausible mechanism linking any such effect with well-established clinical differences would need to be demonstrated. As those who have read a few of my commentaries will know, all sorts of theories have been advanced about all sorts of things in psycho-pharmacology over the last 50 years. Few have proved ‘true’, even when they emanated from independent sources. All the RCTs originate from the pharmaceutical manufacturer and are thus even less likely to be corroborated and substantiated by additional independent research (6-8).

The evidence adduced in relation to the supposed therapeutic effect, never mind superiority of, quetiapine is pathetic; but more of that later.

The key issue is this: is there any sound evidential basis for supposing quetiapine is, despite being so-like promazine pharmacologically, somehow magically different in a way we do not yet understand, that confers advantage? Pigs might fly.

The 'fast-off' idea

The main explanation put forward is the so-called 'fast-off' idea (see also discussion of another unconvincing ‘explanation’ re 5-HT2A receptors here). This idea suggests that the key difference with atypical antipsychotics is that they dissociate from their binding with the D2 receptor much more quickly, like 100 times more quickly, than the traditional antipsychotics (9, 10). Put simply, the evidence for this is unconvincing and not well replicated and the techniques used to establish this are new, uncertain, and of unproven reliability. The most recent research suggests little or no association between ‘fast-off’ properties and ‘atypical’ characteristics, whatever they are conceived to be (11).

It is also notable that most of the publications on this topic seem to come from one author, Seeman: that should always make one sceptical, just like Meltzer and the 5-HT2A story. It is premature to justify, or base, any clinical actions on such a nebulous notion. The notion that the weaker the D2 binding, the better it works, reminds one of homeopathy!

A medline search for ‘atypical antipsychotics’ and ‘fast-off’ yields only 6 results since Seeman’s 2002 paper: one would think, after 15 years, if there was mileage in this idea, that the drug company would be throwing some of their billions of dollars of profits at researchers to ‘prove’ it. Or do they know full-well that it is baloney?

Then again, if you are making that many billions why would you care about anything!

PET Studies show low and transient D2 binding (12-16) and minimal effect on prolactin.

The number of publications doubting the efficacy of quetiapine is small: here is one which is a bit feeble, and does not even mention histamine (17):

https://www.nps.org.au/australian-prescriber/articles/concerns-about-quetiapine-3#r4

‘Evidence’ from clinical trials

Antagonism of H1 receptors improves appetite, sleep and anxiety. In the frequently used Montgomery-Asberg depression rating scale***, appetite, sleep, anxiety, and concentration (often impaired due to anxiety) each rate up to a max of 6 points (severe) out of a total of ten items (i.e. max total score id 60 pts). Thus, they make up 24 pts. out of the total of 60. The Hamilton scale is little different.

*** Another example of a shit rating scale: it has almost no rating of the core symptoms relating to psychomotor retardation like drive, energy, motivation, interest; nor of anhedonia, enjoyment, pleasure, satisfaction. So it is rating anxiety more than biological depression.

The claimed improvements from quetiapine (11 papers in a recent ‘meta-analysis’, all drug-company sponsored (18), see also (19-21)) average only 4-5 pts ***. A child from the bottom of the maths class can figure out that easily adds up to 5-10 points, just from sedative effects. Not rocket science is it!

*** Incidentally, the usual variations of ‘inter-rater reliability’ (i.e. how different the scores will be if 2 raters asses the same patient) is of that order, viz. ~ 5 pts. I very much doubt if any of those trials tested their inter-rater reliability. Such points help one to appreciate that the scientific standard of these trials is extremely poor.

Look at the scale for yourself: https://psychology-tools.com/montgomery-asberg-depression-rating-scale/ see how small the changes in appetite, sleep, anxiety and concentration need to be to produce this small degree of improvement.

It should also be noted that most of the studies on schizophrenia emanate from China. The evidence of fraud and bias is even worse for Chinese studies than others (22, 23)

And that is called evidence.

These improvements are most convincingly explained by its sedative antihistamine property which is substantiated by the fact that the improvement is manifest in less than one week, and at low doses (< 50 mg daily). Such doses can only be effecting H1 receptors (thus producing sedative, anxiolytic and sleep promoting changes), at those doses there would be absolutely no effect on D2 (or any other) receptors. A recent large study of 1,000 patients showed most managed to take it for less than 3 months and only at a dose of 25 – 40 mg a day (21, 24), and the prominent effects were, wait for it, you guessed, yes, tiredness and sleepiness!

As far as schizophrenia is concerned the latest summary from the Cochrane review is: ‘Most data that have been reported within existing comparisons are of very limited value because of assumptions and biases within them’ (25). And much data emanates from China where fraud and bias is even worse (22, 23). Like I said before, just no good evidence of different or superior effectiveness.

Conclusion

  1. No reliable pharmacological data exists that would even suggest quetiapine is likely to be any use for depression except as an anti-histamine and therefore sedative and anxiolytic. But doxepin would be better and 100 x less expensive.
  2. No reliable clinical data exists indicating useful superiority for schizophrenia.
  3. No reliable clinical data exists indicating usefulness for any form of depression.

Quetiapine is an very expensive drug of minimal usefulness. The world would probably be better off without it. I suggest clinicians who ‘believe’ this works might read the story of Sir Arthur Conan Doyle and the ‘Cottingley Fairies’.

References

1.         Kim, SF, Huang, AS, Snowman, AM, Teuscher, C, et al., Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA, 2007. 104(9): p. 3456-9.

https://www.ncbi.nlm.nih.gov/pubmed/17360666

2.         Salvi, V, Mencacci, C, and Barone-Adesi, F, H1-histamine receptor affinity predicts weight gain with antidepressants. Eur. Neuropsychopharmacol., 2016.

http://dx.doi.org/10.1016/j.euroneuro.2016.08.012

3.         Nasrallah, HA, Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol. Psychiatry, 2008. 13(1): p. 27-35.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17848919

4.         Kroeze, WK, Hufeisen, SJ, Popadak, BA, Renock, SM, et al., H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology, 2003. 28(3): p. 519-26.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12629531

5.         Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol, 2007. 151(6): p. 737-48.

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707253/pdf

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17471183

6.         Ioannidis, J, Lies, Damned Lies, and Medical Science. Atlantic, 2010. November 17th.

http://www.theatlantic.com/magazine/archive/2010/11/lies-damned-lies-and-medical-science/8269/

7.         Ioannidis, JP, Why most published research findings are false. PLoS Med, 2005. 2(8): p. e124.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16060722

8.         Naci, H and Ioannidis, JP, How good is “evidence” from clinical studies of drug effects and why might such evidence fail in the prediction of the clinical utility of drugs? Annu. Rev. Pharmacol. Toxicol., 2015. 55: p. 169-189.

9.         Seeman, P, Atypical antipsychotics: mechanism of action. Can. J. Psychiatry., 2002. 47(1): p. 27-38.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11873706

10.       Vauquelin, G, Bostoen, S, Vanderheyden, P, and Seeman, P, Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism. Naunyn. Schmiedebergs Arch. Pharmacol., 2012. 385(4): p. 337-72.

https://www.ncbi.nlm.nih.gov/pubmed/22331262

11.       Sahlholm, K, Zeberg, H, Nilsson, J, Ögren, SO, et al., The fast-off hypothesis revisited: A functional kinetic study of antipsychotic antagonism of the dopamine D 2 receptor. Eur. Neuropsychopharmacol., 2016. 26(3): p. 467-476.

12.       Nord, M, Nyberg, S, Brogren, J, Jucaite, A, et al., Comparison of D dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects. Int J Neuropsychopharmacol, 2011. 14(10): p. 1357-66.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21477416

13.       Vernaleken, I, Janouschek, H, Raptis, M, Hellmann, S, et al., Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas. Int J Neuropsychopharmacol, 2010. 13(7): p. 951-60.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20392299

14.       Nikisch, G, Baumann, P, Kiessling, B, Reinert, M, et al., Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine. J. Psychiatr. Res., 2010. 44(12): p. 754-9.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20176367

15.       Sparshatt, A, Taylor, D, Patel, MX, and Kapur, S, Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. The Journal of clinical psychiatry, 2011. 72(8): p. 1108-1123.

16.       Sparshatt, A, Jones, S, and Taylor, D, Quetiapine: dose-response relationship in schizophrenia. CNS Drugs, 2008. 22(1): p. 49-68; discussion 69-72.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18072814

17.       Brett, J, Concerns about quetiapine. Aust Prescr, 2015. 38(3): p. 95-7.

https://www.ncbi.nlm.nih.gov/pubmed/26648630

18.       Suttajit, S, Srisurapanont, M, Maneeton, N, and Maneeton, B, Quetiapine for acute bipolar depression: a systematic review and meta-analysis. Drug Des Devel Ther, 2014. 8: p. 827-38.

https://www.ncbi.nlm.nih.gov/pubmed/25028535

19.       Maneeton, N, Maneeton, B, Woottiluk, P, Likhitsathian, S, et al., Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther, 2016. 10: p. 259-76.

https://www.ncbi.nlm.nih.gov/pubmed/26834458

20.       McIntyre, RS, Muzina, DJ, Adams, A, Lourenco, MT, et al., Quetiapine XR efficacy and tolerability as monotherapy and as adjunctive treatment to conventional antidepressants in the acute and maintenance treatment of major depressive disorder: a review of registration trials. Expert Opin Pharmacother, 2009. 10(18): p. 3061-75.

https://www.ncbi.nlm.nih.gov/pubmed/19954275

21.       Pringsheim, T, Gardner, D, and Patten, SB, Adjunctive treatment with quetiapine for major depressive disorder: are the benefits of treatment worth the risks? BMJ, 2015. 350: p. h569.

https://www.ncbi.nlm.nih.gov/pubmed/25739588

22.       White, J, Fraud fighter: 'Faked research is endemic in China' New Scientist, 2012(2891): p. http://www.newscientist.com/article/mg21628910.300-fraud-fighter-faked-research-is-endemic-in-china.html.

23.       Miyar, J and Adams, CE, Content and quality of 10,000 controlled trials in schizophrenia over 60 years. Schizophr. Bull., 2013. 39(1): p. 226-9 https://academic.oup.com/schizophreniabulletin/article/39/1/226/1889747/Content-and-Quality-of-10-000-Controlled-Trials-in.

https://www.ncbi.nlm.nih.gov/pubmed/22290267

24.       Pae, CU, Wang, SM, Han, C, Lee, SJ, et al., Quetiapine augmentation for depression: dosing pattern in routine practice. Int. Clin. Psychopharmacol., 2015. 30(1): p. 54-8.

http://www.ncbi.nlm.nih.gov/pubmed/25371174

25.       Asmal, L, Flegar, SJ, Wang, J, Rummel-Kluge, C, et al., Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev, 2013. 11: p. CD006625.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=24249315

This section on diurnal variation of mood was added in 2017, after talking to someone with depression over Skype, and explaining about diurnal variation. That reminded me of an analogy I used.

Persistent diurnal variation of mood is one of the more reliable markers of a biological depression. However, something I have observed over the years, which does not seem to crop up in the literature, is this: the improvement of mood that occurs in the afternoons and evenings, and the return of severe symptoms on waking next morning, is something that gradually gets less noticeable if the illnesses becomes more severe and has been present for some time. In other words, as the illness is developing, diurnal variation is most noticeable; if-and-when the illness reaches a severe degree, then diurnal variation becomes less noticeable. People just feel like ‘death-warmed-up’ the whole time.

The converse is also true. As more severe illnesses start to improve and respond to treatment, the early improvement is usually most noticeable in the afternoons and evenings, but then, when people wake up next morning, they feel as bad as ever. If you ask someone with severe illness ‘what is your first thought about the day ahead when you awake’, the answer is frequently ‘OMGAD’ (Many suffers guess that acronym immediately, I spell it out below***). Hence the heading of this piece, ‘A cruel trick’. I am sure that this phenomenon has been responsible for many people giving up on treatment, or despairing of improvement, because they feel better in the afternoon and think the illness is improving, only to wake up as-bad-as-ever the next morning. If no one has provided the above explanation that phenomenon is a profoundly discouraging experience.

Remember the ‘waves on the beach’ analogy above, remember to compare like with like, i.e. afternoons with afternoons, or mornings with mornings, and remember to compare averages of several days, with a gap of a few days in between, to judge change. Also, as I often commented to patients ‘I do not care how you feel’. That made people stop and listen! Instead I want to know what you have done, compared to before. This point was illustrated only a few days ago, in another skype ‘consultation’: ‘How are you going’? ‘I am more anxious …’. This person felt they were not improving. But a couple of brief questions made things clear. They had in fact managed to go shopping, alone, twice in that week, in order to get the ingredients to cook a meal (for the first time in a while) and also been to a drinks party and ‘coped quite well and enjoyed it, a bit’. And there was more! No wonder anxiety had increased. In relation to this remember ‘Salami tactics’ above, and the aphorisms, ‘Slow and steady wins the race’, ‘Do not try to run before you can walk’, and ‘Do not bite off more than you can chew’.

If people are doing more activity that is strong evidence they have more drive and energy: if that core symptom is improving one can be quite sure they are getting better. As president Nixon is quoted as saying, ‘When you’ve got them by the balls, their hearts and minds are sure to follow’.

Enough said.

The acronym: *** ‘Oh my god, another day’.