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

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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

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