Atypical Anti-Psychotics and Humpty Dumpty
This commentary covers the history and concepts behind the poorly defined (almost meaningless) term “atypical antipsychotics”. It discusses the woeful lack of evidence for the claimed properties, superior effectiveness and lesser side effects of these drugs over previously existing drugs; it reviews the (lack of) evidence for the notion of meso-limbic selectivity and the supposed role of post-synaptic serotonin receptors. The hundreds of billions of dollars these drugs cost is outlined as background to assessing which of this disparate batch of drugs might, just possibly, constitute a significant advance.
It is concluded that 1) No reliable replicated scientific evidence exists to support the claims that these drugs are different or better: 2) any opinions about these new drugs that are reached are based on such limited quality and quantity of evidence that they constitute little more than best guesses: 3) patients who are being given these drugs are effectively guinea pigs, but no accurate scientific data is being gathered about the outcome of the experiment (which is thus unethical); i.e. There is effectively no quality post-marketing surveillance which is probably the most scandalous aspect of the whole saga.
- Since the original version of this commentary was posted on my website some months ago I have responded to a request to write a very much condensed version for the Carlat psychiatry report in the USA(1). This slightly amended version of the commentary was posted at the beginning of 2013.
Anyone familiar with my writing will know that scientific evidence indicates that one cannot assign a high level of reliance on drug trials. Trials purporting to show the equivalent effectiveness of new drugs compared to older drugs are hardly worth the paper they are written on. That fact is acknowledged by the extensive caveats and reservations expressed in almost all the review papers and meta-analyses referenced below.
Similarly, genuinely different or superior drugs, if they exist, may only be so in a subset of patients and may not show that difference in an unselected group. Such differences may only be evident to clinicians who treat patients over prolonged periods of time with a variety of drugs. However, claims of such difference/superiority derived from practical experience must always be regarded with caution because most so-called expert opinion and experience is merely an exercise in confirmatory bias and self-delusion. Therefore, the more recent meta-analysis discussed below should not necessarily be taken to indicate that none of these drugs have useful advantages (as opposed to trivial and inconsequential ones). However, these analyses do reflect the fact that the majority of those expert in the analysis of this kind of work are in close agreement about the fact that any touted advantages are minimal.
This commentary is not in itself a critical analysis of efficacy data. It only aims to note the various recent meta-analyses and comments from mainstream opinion. Also, it does not discuss in detail the therapeutic indications, the individual drugs, their mechanism of action, or their receptor profile: that may be covered in a future commentary.
The success of international pharmaceutical companies in persuading the medical profession and public of the value and usefulness of the newer generation of anti-psychotic drugs represents one of the most spectacularly profitable advertising and sales exercises in the medical arena. The uncritical acceptance by doctors of these drugs, and doctors’ incompetent and harmful use of them (much of it “off-label”, especially in the USA), is a shameful episode in the history of the medical professions’ naively dysfunctional relationship with the pharmaceutical industry. The medical professions’ lack of disciplinary action against the professors, researchers and academics who have been complicit in these decades of deceit, dishonesty (e.g. “ghost writing”) and fraud may come to be regarded as the most enduring condemnation of the professions’ amorality for years to come.
It is appropriate to start by outlining a few central issues about the so-called “class” of drugs referred to as “atypical anti-psychotics” (there are various names for them, perhaps the most used currently is SGAs (FGA/SGA, i.e. first/second generation anti-psychotics). For over thirty years all the new antipsychotic drugs introduced onto the market have claimed to be “atypical” regardless of their pharmacology, which varies so much that they cannot be regarded as “class” at all. No self-respecting drug company sales or marketing person could possibly entertain or condone any publication or advertisement that did not contain repeated use of such words. However what “atypical” means, if anything, and whether such supposed properties have advantages, or differences from, previously existing drugs remains doubtful, and most certainly unproved. Quetiapine is a prime example: it is closely related, structurally and pharmacologically, to both of the archetypal tricyclic neuroleptics, promazine and promethazine. How it can be meaningfully conceived of as “atypical” is a arcane mystery the secrets of which I am not privy to.
The above being so, it is hard to imagine any ordinary person viewing what the pharmaceutical companies have done, in representing and promoting these drugs, as anything other than outright fraud and their relationship with their medical KOLs as a Faustian pact (many courts agree with that, see below).
The idea of atypical anti-psychotics was first mooted about 35 (yes, thirty five) years ago (2)). Various different drugs claim various different sorts of atypical features, which inevitably reminds one of Alice in Wonderland when Humpty Dumpty said, “words mean what I choose them to mean, nothing more and nothing less” (3).
Atypicality is an advertising executive’s dream come true. Atypicality seems to have moved through several phases of pseudo-explanation: first, meso-limbic selectivity, then 5-HT2A mechanisms, then dopamine dysregulation. Despite the fact that development of 5-HT2A antagonists has fizzled out, Meltzer, a prominent theorist and commentator (4), has just published a review paper (2011) extolling that notion, “The role of serotonin receptors in the action of atypical antipsychotic drugs”.
The evidence supporting the notion of atypicality remains as weak now as it was 30 years ago.
There is one simple rule in science that can be applied when novel claims are made; for drugs that is usually less side effects or faster onset of action. If the claims are valid then the evidence supporting the claim will accumulate and become stronger as time progresses. If there is not a clear trend over time of independently replicated scientific work strengthening the initial claim then it is almost certainly not true: for a more detailed analysis of how that notion relates to drug trials see Siontis et al (5).
The following point is one that has been made about comparisons between the old TCAs and the SSRIs. It is even more applicable to comparisons of the so-called SGAs with the FGAs. It is logically fallacious and statistically meaningless to compare (or even think about) two arbitrarily grouped entities with one another, as some meta-analysis studies do. You cannot compare a basket of mixed fruits with a basket of oranges, and even less with a basket of mixed vegetables.
SGAs are not, either structurally or pharmacologically, a homogenous group of drugs, SGAs are not a homogenous group of drugs, repeat after me, SGAs are not a homogenous group of drugs. They are not a “class”. Unfortunately, relentless repetition of the tag SGA has its effect and doctors collude: it is complicated and doctors may not have the time to master it.
It really concerns me that researchers persist in referring to these drugs as if they were a homogenous class (i.e. which they do just by calling them SGAs, or whatever), just look at the titles of the cited references.
SGAs have neither a proven, nor a single, established common mode of action. Comparing them with any other group of drugs (homogenous or not) is statistically and logically meaningless. It is just utter nonsense. The only valid comparison is between one drug and another. The only logical and meaningful comparison would be a long-term comparison of one of the older drugs against one of the newer drugs; e.g. see Tiihonen (6). Needless to say, with the huge dollars at stake, it would actually be quite possible for this to be done, but it is not in the interest of any drug company to do it. So, the silliness continues.
The evidence produced to support the claims for superiority of most, if not all, SGAs is marginal at best and dishonest at worst (7, 8). There is not one single major advantage the validity of which has been unequivocally demonstrated by independently replicatedscientific research. A recent analysis of FDA data on these drugs illustrates, yet again, how it continues to be appropriate to be cynical and cautious (7).
All these trials last a mere 4-6 weeks: the drugs are continued for years. There is no systematic collection of subsequent data on long term complications, side effects or toxicity, never mind long term superiority/efficacy. It is hard to convey concisely how spectacularly that represents poor science and lack of due diligence (cf. Tiihonen; an exception to this rule and interesting evidence for a superior long term benefit of clozapine (6)).
However, the SGAs have some major disadvantages (weight gain, metabolic syndrome/diabetes, sedation). Anyone who has read my writing about science will appreciate the absolute necessity of independent replication of both animal experiments and human drug trials. The lack of replication indicates strongly there is no substantive evidence that any of these drugs possess advantageous properties.
You do not even have to be a cynic to suggest that the only thing about SGAs that is atypical is the cost: they are between 10 and 100 times more costly *** than the previously existing drugs. If an extrapolation is made from the Pharmaceutical company annual report figures, quoted in this commentary, we can state confidently that the total global cost of the new so-called atypical antipsychotic drugs is now many hundreds of billions of dollars. That would impress even the bankers at Lehman Brothers, as a cash cow. See below for details of the dollars involved from Pharmaceutical company reports.
*** Ten times if you look at the “pharmacy” cost, more like 100 times if you consider the actual “ex-factory” cost. You can probably get chlorpromazine for $10 per thousand tabs, but the SGAs are more like $1000. i.e. cost ratio of 100:1.
There are various reviews about these drugs that have been published recently as attested to by these references (4, 9-17), and they contain some useful summary information. I quote a few conclusions from the above references to illustrate that they are being represented fairly and that they are beset with caveats “maybe, perhaps, but, however …”:
“Best available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks. … data … of very limited value because of assumptions and biases within them”
“Olanzapine may be a somewhat more efficacious drug than some other second generation antipsychotic drugs”
“Zotepine may be less effective than clozapine and associated with more movement disorders and higher prolactin levels, but the evidence base is too small and prone to bias.”
“We found amisulpride may be somewhat more effective than ziprasidone, and more tolerable in terms of weight gain and other associated problems than olanzapine and risperidone. These data, however, are based on only ten short to medium term studies and therefore too limited to allow for firm conclusions.”
“Ziprasidone may be a slightly less efficacious antipsychotic drug than amisulpride, olanzapine and risperidone. Its main advantage is the low propensity to induce weight gain and associated adverse effects. However, the high overall rate of participants leaving the studies early limits the validity of any findings.”
However, what particularly concerns me is that most of the reviews do not seem to take sufficient notice of the biases in the data, never mind the outright deceits, and many of them do not evince a sufficient understanding of receptor pharmacology (see Richelson for an explanation of receptor pharmacology (11)).
It is important to keep repeating that no meta-analysis can be better than the original data upon which it depends (18, 19). That is the old computation saying “GIGO”, “garbage in, garbage out”. What would Charles Babbage have thought? well, we know, because he told us.
“On two occasions I have been asked,—”Pray, Mr. Babbage, if you put into the machine wrong figures, will the right answers come out?” … I am not able rightly to apprehend the kind of confusion of ideas that could provoke such a question.”
Charles Babbage, Passages from the Life of a Philosopher.
I think we can conclude safely that he would have though such methodology came from people who were, shall we say, “in the juvenile phase of their scientific developement”.
When there is serious doubt about most of the data, and indisputable evidence that a significant proportion of it is actively misleading and some of it decidedly deceitful (e.g. (8)), then it is wise to go with what various authors have suggested is in keeping with the evidence, which is to adopt the default position that most of this medical data leads to erroneous conclusions (20-29). The preceding list of references is long. That is partly to emphasize the number of scientists who agree with this proposition, but also to enable readers to locate a few references to look at themselves. Not all references will be accessible for all readers, but there is a good chance that you will be able to find full text of at least a few of them if you try. For information about how anyone can easily access the scientific literature see my commentary entitled “Scientific Information” [link].
When the BMJ editor stepped down in 2005 he stated, in the context of being deceived by drug companies, that it took him “almost a quarter of a century editing for the BMJ to wake up to what was happening” (30). Whilst I applaud him for that frank admission it nevertheless reveals that he, like many doctors, was trusting and naive. I have no reason to believe that, in general, the authors of these meta-analysis papers are much different: in fact, I have good reason to think that they are not any less susceptible to deception. For example, neither of the recent reviews referenced above mentions the evidence of deception and dishonestly in relation to the risperidone trials detailed by Huston et al., although one discusses bias specifically in relation to risperidone. I enquired of the authors why there was no mention of the Huston report and Professor Leucht stated they were not aware of it. That serves as a good illustration of how difficult it is to find all the relevant literature. The fact that doctors and researchers now need to go actively seeking evidence of dishonesty, if they are to do a good review, shows how far medical science has sunk into the mire. This applies even to groups like Cochrane who specialize in literature reviews and are experienced in ferreting out relevant literature.
The point about error and bias is particularly relevant in view of the fact that all of the differences being discussed between these drugs are small. They are of the order of magnitude that we know well are often generated by observer errors, bias, and the magnitude of difference regularly generated by the sponsorship effect (7). The authors of the respected Cochrane Database Review have recently stated the following:
“In our opinion, the SGAs are not the breakthrough that industry would like to maintain. … However, these drugs are important contributions to treatment, and most psychiatrists, let alone patients, would probably not want to do without them.” (17).
Other British commentators suggest their fall from grace is already in progress, at least on that side of the pond (31). The American view of these drugs seems to be more enthusiastic and less critical.
The recent British Association for Psychopharmacology (BAP) paper (32) “Evidence-based guidelines for the pharmacological treatment of schizophrenia” represents an influential British view which concludes that there is no efficacy benefit for SGAs over FGAs in the acute treatment of first-episode schizophrenia. The following lengthy (unabridged) quote makes an important point:
“No double-blind trial comparing an SGA with an FGA in the acute treatment of first-episode schizophrenia has shown an efficacy advantage for the SGA, with the single exception of a head-to-head, first-line treatment trial of clozapine versus chlorpromazine conducted in China*** which showed a small, significant advantage to clozapine (33). A meta-analysis of RCTs in the early phase of psychosis found no differences between the FGAs and SGAs tested, in terms of acute symptomatic change or long-term discontinuation. However, there were differences in side-effects profiles, with a greater risk of weight gain for patients prescribed SGAs and a greater risk of extra-pyramidal symptoms (EPS) in those treated with FGAs, most commonly haloperidol. These results challenge the almost exclusive use of SGAs for the treatment of first-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of SGAs in youth for non-psychotic disorders.”
*** one has to be naïve to trust much of what comes out of China, read this link and you will see why (34).
There is (double-blind controlled trial) evidence that Clozapine might possibly be a little better for “treatment resistant (TRS)” schizophrenia, its superiority for a proportion (~30% of those classified as TRS) is thought to have been established against FGAs (35-37) and SGAs (38, 39). Although as clinicians we see individual cases of dramatic improvement with clozapine it may be that this creates an unwarranted “selective attention” bias to recalling such cases; it seems controlled trials indicate such responses are not so much the rule but more the exception. I might note here that I do not claim extensive experience of treating TRS schizophrenia, these comments summarize and reflect the received current wisdom, which longer term readers will appreciate I do not always concur with.
This extract (BAP again) makes it clear the definition of TRS is rubbery and the degree of improvement, in the modest percentage who do improve, is small, often very small.
“TRS has a heterogeneous presentation in terms of symptom and behavioural profile. One limitation of the evidence base for prescribing is that the definition of response in clinical trials involving people with TRS has tended to be a 20% or greater reduction in total BPRS/PANSS score, which may fall short of a clinically relevant change; in acutely ill, psychotic patients, a 20–30% reduction in total PANSS score corresponds to a Clinical Global Impression (CGI) rating of ‘minimally improved’, the smallest improvement considered clinically meaningful. The clinical relevance of such a responder criterion in patients with ‘treatment- resistant’ illness is more uncertain. Overall symptom severity may be less relevant in this group than other outcomes, such as a reduction in ‘target symptoms’ that are causing distress or disability, an improvement in disturbed behaviour, or increased level of engagement in therapeutic and social activities.”
The editor of the British J of Psychiatry, Peter Tyrer has also made similar points in “The spurious advance of antipsychotic drug therapy” (40, 41).
It is worth noting concerning the, “greater risk of extra-pyramidal symptoms (EPS) in those treated with haloperidol”, that it is difficult for doctors dealing with distressed and treatment resistant patients to avoid the temptation of giving a larger dose of a drug in order to get an improvement. I observed early in my career that once the total dose of chlorpromazine exceeded 1,000 mg doctors were much more likely to switch to haloperidol. It does not seem so excessive to give 20 mg of haloperidol as it does to give 1500 mg of chlorpromazine. I think that explains much of the observation above, that haloperidol appears to have more extra-pyramidal side-effects and drug companies set up their trials to take advantage of that.
Finally, there is one fundamental argument which suggests none of these drugs are superior, and indeed that some hardly work at all. As observed above these drugs do not constitute a class of drugs, structurally or pharmacologically. They have a mixed bag of properties with potencies at potentially relevant receptors that differ by at least two orders of magnitude (42-44). That much variation certainly takes them frequently out of the range of relevant functional effect. If they really are all superior, as claimed, then it cannot possibly be because of the properties assigned to them. They must have some other common property that is as yet unknown. That is speculation and is highly unlikely. If on the other hand we accept they are pharmacologically disparate then the most parsimonious explanation for their claimed/apparent superiority (for some/most of them) is that it is an observational and methodological error.
And Alice said to Humpty Dumpty “this is getting sillier and sillier” ***, “When I use a word,” Humpty Dumpty said in rather a scornful tone, “it means just what I choose it to mean – neither more nor less.”(3).
*** Yes, I know, she actually said “curiouser and curiouser”, which, incidentally, Dodgson meant to be solecistic.
Professor Leucht who wrote the Cochrane review (17) also wrote this paper (45) in which he pointed out the absurdity of the apparent demonstration that A is greater than B, is greater than C, which is greater than A. It reminds one of “Penrose stairs”, the visual illusion of the staircase that goes up and up only to rejoin itself at the bottom.
When the major caveats outlined above are taken into account it is difficult to agree with the Cochrane Database Review statement that the SGAs are “important contributions to treatment”.
There may be areas in which they represent improvements, but most of these are small improvements of doubtful or trivial clinical meaning (46), neither the patient nor any family is likely to notice any difference. They are counterbalanced by other side-effects which represent not just disadvantages, but sometimes major problems (47-49). On balance it is questionable whether there is any net gain, especially because doctors are lost and bewildered in the chaos of misinformation and deceit, so most of them cannot know, and do not know, which drug might actually possess some real small advantage.
And all of this at a colossal cost. Indeed, by the time most people read this the total world expenditure on SGAs will be close to one trillion dollars (1,000 billion or a million million).
It would be grossly negligent not to consider the question of whether our health dollar could be deployed to better effect elsewhere.
There are some fundamental questions to consider concerning these drugs: one is whether the notion of atypicality is defined adequately and has a proper meaning and a scientific basis, another is, if it exists (i.e. if there is some meaningful difference in mechanism of action between FGAs/SGAs) does this translate into useful clinical differences for patients? It is important to understand at the outset that there is not a clear positive answer to either of those questions. Not a reassuring basis for the expenditure of one trillion dollars on SGAs.
A brief recapitulation concerning the history and basis of the notion of meso-limbic selectivity is appropriate. The idea that schizophrenia was related to excess dopamine transmission in the meso-limbic areas, as opposed to the nigrostriatal areas, was formulated in the early 1970s, and expounded in a much cited paper (50, 51). At that time the striatum was thought to be concerned only with motor control. However, as is so often the case when one looks closely in medical science, there was a preponderance of presumption and a dearth of direct evidence. Needless to say the situation is not so simple. Thus arose the proposed dichotomy, which was presumed rather than proved, that drugs exhibiting meso-limbic selectivity, that is to say they produced a lesser blockade of the motor nigro-striatal pathways (sometimes called A9 vs. A10 pathways), would have greater efficacy and less side effects.
The SGAs did appear to exhibit modest meso-limbic selectivity in earlier studies using low doses in animals (52-56). Obviously, low doses in animals does not necessarily equate with therapeutic doses in humans. It is not established that normal doses in humans exhibit such selectivity. Newer positron emission tomography (PET ) evidence in humans goes directly against that idea (16). In 1996 Schotte et al found no regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas for any of the test compounds: risperidone, 9-OH-risperidone, haloperidol, pipamperone, fluspirilene, clozapine, zotepine, olanzapine, quetiapine, sertindole, asenapine, ziprasidone (57). Other more recent PET studies in humans also clearly indicate that the occupancy of most of them, including: olanzapine, quetiapine, aripiprazole, are no different in the two areas (58-64).
As an aside, let us pose a question. You are in charge of research for a drug company, you can easily afford to do PET studies which would show that your drug indisputably possessed real differences in selectivity at therapeutic doses in humans. This would be bells and trumpets stuff, you would be falling over yourself to get such studies done and shout about them from the highest roof tops. However, the reality is that there are extremely few published studies by manufacturers. Draw your own conclusions. Were the studies were done but never published, because they were negative?
In summary: even if there is some, as yet undemonstrated, meso-limbic selectivity for a minority of these drugs it seems, for most of them, it is small and of dubious significance or benefit in real life.
The influence of 5-HT2A, 2C, 1A etc. receptors on DA pathways is still a prominent idea in the general literature underpinning the idea of atypical antipsychotic drugs, although new research publications on 5-HT2A seem to be declining and development of such drugs seems to have terminated after some have failed in trials (65).
Our understanding of the inter-relationships between different neuronal pathways of the brain remains at a fairly simple level. One thing we do know is that there is a high degree of inter-relatedness, almost all pathways have various feedback mechanisms which maintain the stability of the system in both the short and long term. Generally speaking the level of activity of neuro-transmitters in normal functioning varies over quite a narrow range. The magnitude of change brought about by external interference with drugs is usually much larger than that normal physiological range. The feedback mechanisms that maintain the stability of the system are by their very nature, of being part of this homeostatic system, generally only able to effect adjustments within that limited physiological range. It is therefore is reasonable to assume that pathological changes, which by definition are non-physiological, as well as the changes brought about by drugs, tend to overwhelm those negative feedback mechanisms. This being so, it is reasonable to make the initial assumption that feedback mechanisms will only produce relatively small changes in the activity of the pathways with which they interact.
There is discussion of other aspects of this general negative feedback principle in other commentaries. Thus, to the extent that 5-HT2A/2C/1A, or any other feedback receptor, may influence the activity of dopamine pathways the magnitude of this change is likely to be small (i.e. within the normal physiological range), of limited duration and can appropriately be referred to as modulation. It is fine-tuning. If, and that is a big if, the fundamental pathology of schizophrenia is intimately and primarily to do with dopamine levels, then interfering with pathways that only fine tune dopamine levels is likely to be insufficient to make any substantive difference to the overall pathology. The, at best modest, effect of APs generally, and of SGAs over FGAs, is testament to that.
A good example of the minimal effect of 5-HT1A receptors is that of serotonin toxicity, my special area of expertise. It is clear that drugs that affect 5-HT1A auto-receptors have minimal, if any, affect on serotonin toxicity or its manifestations. That suggests they deal with fine tuning and are overwhelmed by the larger pathological changes that occur with drugs which invoke toxicity.
Since there is little evidence that 5-HT2A antagonists directly benefit schizophrenia (65)another possibility is that they could be of some benefit by an indirect influence on dopamine levels in some other area of the brain, like the frontal cortex. There is evidence that 5-HT has a negative feedback influence on various dopamine pathways, including frontal cortical, and that is mediated through various 5-HT receptor sub-types (66). Therefore blocking them removes that inhibition on frontal dopamine levels. However, whether that occurs in those experiencing schizophrenia, and whether that effect is maintained over longer periods of time, and whether that does any good, is a more complex question for which there is little substantive supporting evidence.
And there is more: not only is there is no good evidence that 5-HT2A antagonists directly benefit schizophrenia, neither is there good evidence that 5-HT2A agonists cause, precipitate or exacerbate schizophrenia (e.g. LSD). NB agonist directed trafficking (ADT) may be relevant here (see refs for explanation and reviews re ADT (67-70), but even 5-HT2A agonists drugs like LSD and bromocriptine, that do (sometimes) cause hallucinations, do not convincingly resemble the hallucinations characteristic of schizophrenia, nor are they major precipitators of schizophrenic syndromes. When I was a young doctor in London great numbers of people were taking LSD on a regular basis and yet I never admitted anybody to hospital who I thought had schizophrenia but who turned out to have taken LSD.
If you wish to read a more optimistic view of the hallucinogen model of psychosis in relation to serotonin and schizophrenia then see Geyer (71). However, in my view Geyer seems to see form and substance where there are only shadows: for instance, the 3rd person auditory hallucinations of schizophrenia are as different as chalk is from cheese compared to the visual hallucinations characteristic of LSD etc. To equate the two is like regarding all forms of chest pain as heart attacks.
We need to remind ourselves that many drugs of abuse like amphetamines, ecstasy (MDMA), LSD and others have all been stated to cause symptoms that emulate schizophrenia. Researchers in their eagerness to bolster the validity of biochemical models of schizophrenia have made all sorts of analogies. Since the above drugs have disparate mechanisms of action, and on different pathways in the brain, it is unlikely that such analogies explain anything much. It is noteworthy that no individual drug from the above list stands out as being more likely to be implicated in the generation of schizophrenia-like symptoms or syndromes. It therefore seems that such ideas have little heuristic validity or explanatory or predictive power (72-76).
The most prominent recent review (2011) on this topic “The role of serotonin receptors in the action of atypical antipsychotic drugs” (4) is by Meltzer, the doyen of SGA theorizers and commentators, he concludes:
“The evidence discussed here … strongly suggests that more potent 5-HT2A receptor inverse agonist and weak D2/D3 antagonist actions of many atypical APDs are the key determinants of their efficacy and tolerability in schizophrenia.”
It may seem audacious to criticize an eminent professor for whom this subject appears to be his life’s work: see
However, readers may judge for themselves.
Generally: Meltzer’s paper (4) concerns animal models of particular aspects of schizophrenic symptoms (rats with schizophrenia has always been a dubious and tortured analogy that has not borne much fruit, see Feifel (77)) and the argument depends on assumptions that known mechanisms of these drugs’ actions are their only mechanisms of action, which is unlikely (never mind any metabolites). There are uncertainties and dubious analogies that make this notion unconvincing, as well as apparent “cherry-picking” of data.
For example, it seems perverse to omit the very FGAs that might contradict the hypothesis. Chlorprothixene and chlorpromazine are probably more potent 5HT-2A antagonists than some SGAs, including clozapine, the proto-typical atypical. Note that I say “probably” because receptor affinity data is not necessarily sufficiently accurate to make confident pronouncements about the relative potency of drugs, and furthermore, as alluded to above, the uncertainties relating to the downstream effect of drugs, including agonist directed trafficking, introduce yet further uncertainties (affinity does not always equate with efficacy for a multitude of reasons).
Even if all other technical and scientific aspects of the paper are sound it remains a speculative and poorly supported thesis.
First, it will be obvious, from the agreed lack of superiority of efficacy of the SGAs, that Meltzer’s argument contains a major fallacy because it assumes that there is a general superiority of efficacy of SGAs. That superiority is unproven, indeed the evidence is so weak it is still under dispute after years of research: so any consequent deductions are but speculations.
Second, consider this quote, from Meltzer’s paper (4), “A recent PET study found that antipsychotic drug-naive first epidsode [sic] schizophrenia patients have decreased binding potential for 5-HT2A receptors in frontal cortex (78).” That reference (78) is one of his own papers from 20 years ago. “Recent”, 20 years ago? I think not. PET studies were in their infancy then and have advanced a lot since, see (79, 80). Even if one knew nothing about this subject one should be suspicious of a statement that quotes a 20 year old reference with no more recent studies to substantiate it.
Third, the data presented in the Meltzer’s paper (4) concerning the ratio of D2 and 5-HT2A receptor activities (see also (81)) of these drugs simply does not take into account the inaccuracies and uncertainties inherent in estimating these properties (80, 82). A brief glance at my commentary on interpreting receptor affinity data will make this clear [link]. In Meltzer’s table 1 (& Fig 1) the quoted values for receptor affinities have no error ranges and are given to a spurious degree of accuracy. Also, there are no clear references cited, nor any discussion of the choice of values (it looks like the data comes from an old 1999 paper (83)). Why is there no more recent data he can adduce to support his case? In a rapidly advancing field such as this an absence of more recent data over the last 12 years makes me very sceptical.
NB The paper by Richtand et al (81) has much more recent and better receptor data (taken, appropriately, from the PDSP database) and shows very weak correlations which do not look at all convincing. However, they still omit various APs (FGAs) like: amoxapine, droperidol, flupenthixol, fluspirilene, perphenazine, prochlorperazine, which are probably significant 5-HT2A antagonists. They make a bewildering number of permutations and combinations of comparisons, e.g. in Table 4:- 5-HT2A/D2, 5-HT2C/D2, 5-HT2A/D3, 5-HT2C/D3, 5-HT2A/D4, 5-HT2C/D4, 5-HT2A * D2, 5-HT2C * D2, D2 (5-HT2A/5-HT1A), D2 (5-HT2C/5-HT1A), D2 (5-HT1A/5-HT2A), D2 (5-HT1A/5-HT2C). None of these produce substantial correlations.
Let us look at his values for olanzapine to start with: Meltzer’s table 1 gives the pKis (log reciprocal of Ki) as, Olanzapine D2 8 and 5-HT2A 8.4, giving a D2/5-HT2Aselectivityratio of 0.4. Skipping over the mathematical errors, like 8 & 8.4 or should it be 8.00 and 8.40, or what? Let us proceed to the choice of these values.
The definitive database for Ki values is the PDSP database which provides the range of HCR values for olanzapine for D2 affinity from 3 to 100 and for 5-HT2A, 2 up to 24. It is quite obvious that if we use various combinations from this range to create a ratio we will obtain ratios that might differ by an order of magnitude from the values given in Meltzer’s table (the old data from 1999 that he seems to be using are from rats, but that is not inherently more accurate than human HCR data, so my point is valid). The figure 1 in his paper then plots these ratios as a graph to produce a straight line relating the values on the two axes. However, since the ratios he obtains are seemingly arbitrarily chosen values from arbitrarily chosen drugs (11 out of 19 drugs used are not even established APs), and without error margins, the values cannot be construed to demonstrate a convincing relationship. The exercise looks like an artifice. For those interested, and have access to Meltzer’s paper I will particularise my criticism. The figure on page 61 covers a range of ratios of approximately 1,000 million fold. The only part of the graph that I think is relevant from the point of view of therapeutic drugs is the small oblong group of dots in the middle which cover the range 0.1 to 10. On a log scale that is a huge difference in the ratios. What this means is that the effect of the drug in the living animal or human is highly likely to be completely irrelevant. The concentration range within which drugs have relevant effects is relatively small and drugs that have a ratio of two effects that is much greater than 100/1 will almost certainly have effects which are either too small to be noticeable, or so great that they are toxic. The small number of outliers right and left hand side of the graph are obviously what enables a moderately straight-line to be drawn. However, I would contend that the only relevant section of the graph is a small centre section, and it would obviously be possible to draw a line in virtually any orientation through that group of points. If it were possible to add in a highly relevant drugs mentioned above, like chlorpromazine and chlorprothixine, then I suspect the graph would be meaningless.
- Meltzer’s paper gives as conflicts of interest “HYM is a shareholder and consultant of ACADIA that is developing ACP-103 for Parkinson’s Disease. … has been a consultant or grantee of Azur, BioLineRx, Cephalon, Cypress, Dainippon Sumitomo, Eli Lilly, EnVivo, Janssen, Merck, Novartis Pfizer, Roche, and Teva.”
That is a lot of potential conflict.
When I asked the editor of the journal to publish a comment pointing out problems in Meltzer’s paper he stated “I’m not aware that the Current Opinion journals have a precedence of allowing such discussion/comment of papers as you suggest.” To which there was only one reply I could give, “Oh- so it not really a scientific journal then.” Perhaps they could re-name it “Current One-Sided Opinion”. It is, of course, a basic principle of science that comment and criticism of published work must be allowed. Post-publication comment by other researchers is at least as important as pre-publication peer review. Science is not like a papal edict, however eminent professors may think they are (cf. Prof Biederman, below, who equates himself with God).
Remember, always: caveat lector (reader, beware!).
Before coming to a conclusion about 5-HT2A receptors and schizophrenia it is useful to step back and remind ourselves again that many drugs, including many FGAs, possess clinically relevant 5-HT2A receptor affinity in humans and have been in use for over half a century. All the following drugs have 5-HT2A Ki values more potent than quetiapine and several other “SGAs”: amoxapine, chlorpromazine, chlorprothixene, droperidol, flupenthixol, fluphenazine, fluspirilene, perphenazine, prochlorperazine, thioridazine, thiothixene, trifluoperazine (data from PDSP data base).
Two specific examples, chlorpromazine CPZ (Ki 2-5 nM), chlorprothixene (Ki 0.4-2.0): more potent than many SGAs! All of these are relevant to my area of expertise, serotonin toxicity, because they are such potent 5-HT2A antagonists that they effectively block ST, both in rats and in humans. So they definitely have relevant clinical activity in the usual doses (PET studies support that too (84)). It should be immediately obvious that if 5-HT2A receptor activity was implicated in schizophrenia then CPZ and chlorprothixene would be perceptibly superior to haloperidol. They do not appear to be, and if they are (but nobody claims to have noticed that in 40 years) then they are a lot less expensive than olanzapine, quetiapine etc!
It appears reasonable to leave this discussion by noting another 2011 review “Serotonin 2A receptor antagonists for treatment of schizophrenia”, which, hardly surprisingly, concludes, “Three previous 5-HT(2A) receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT(2A) receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.” (65).
Has Professor Meltzer spent a long time flogging a dead horse? His paper is not, by any stretch of the imagination, “substantial additional validation”.
We did suggest before that Alice might say, “this is getting sillier and sillier”. On the basis of its pharmacological profile quetiapine qualifies as a moderately selective anti-histamine, rather than an anti-psychotic, and is similar, both structurally and pharmacologically, to promethazine and promazine and loxapine. The fact that it has few and weak actions is verified by its toxicity profile which mirrors its receptor profile as a weak anti-histamine with anti-muscarinic effects, the main effects in OD being sedation and delirium (85, 86). Indeed, we could be in Paris in the 1940s (87, 88): I refer to the history of the discovery of the clinical uses of CPZ by Laborit (89). Note that for all three drugs both their receptor profile, ring structure and 3D configuration are similar. See http://www.drugbank.ca/
See also newer commentary (2017) specifically about quetiapine https://www.psychotropical.com/quetiapine-the-miracle-of-seroquel/
There does appear to be good evidence quetiapine is an NRI via its metabolite N-desalkylquetiapine (aka norquetiapine) (90). That data is from Brian Roth’s lab, he runs the PDSP database, so he knows what he is doing. See also (91), which suggests NET occupancy in primates of only 35% with 300 mg/d quetiapine XR. That suggests insufficient potency to produce any clinical effect. There are no other replications of this result, but the Roth value is a Ki of 12 nM. For approximate comparison reboxetine and nortriptyline are ~ 10 nM and desipramine is ~ 1 nM. I have not found any data to indicate if the desalkylquetiapine plasma levels are usually sufficiently high to make it likely that it is routinely acting as an NRI, but that seems unlikely on the current evidence.
This will be discussed in more detail in a future note.
As one who strongly supports the use of Bayesian reasoning, it has to be said that the strongest conclusion that can be drawn from this data is that the clinical trial process itself is flawed (which is hardly news). In other words, if someone can introduce a drug like quetiapine, that is essentially an antihistamine, and convince medical science is an antipsychotic, then drug trials are probably fallible. I doubt if it has any significant effect other than as an anti-histamine and I would like to see some direct comparisons between it and promazine and promethazine. Talk about “the wheel is come full circle” (Edmund, King Lear).
It is difficult to resist pointing out one further major flaw in this “atypical” line of thinking. There are substantial differences (like orders of magnitude) with most of these drugs between their potency for antagonism of numerous receptors, especially dopamine D2 receptors and 5-HT2A receptors. If only partial blockade of dopamine receptors is part of the secret then many of these drugs are going to exhibit too little/great an effect at 5-HT2A or D2 receptors (also, a therapeutic window has been proposed (63) suggesting the optimal level of blockade at 5HT-2A receptors is 60 to 70%). Quetiapine (Seroquel) is such a weak dopamine antagonist (Ki nM D2=500, 5-HT2A=100, H1=7) that it only blocks dopamine receptors to a maximum of 60% at usual doses (usual maximum dose is cited as < 800 mg/day) (92) and then not for long since its half-life is only around 6 hrs! (but it is about fifty times more potent at H1 receptors, which it swamps at that dose, hence the weight gain and sedation!). For most of the 24 hrs blockade at D2 is minimal, closer to 20%. It is difficult to imagine that has much effect on anything (even in overdose it shows no DA antagonism effects!).
It is also interesting that there are few reliably documented cases of typical NMS with quetiapine (and, of course, the same is true of promazine and promethazine), some are doubtful and/or in the presence of gross brain damage: it certainly appears it might be less common than with other FGAs or SGAs. That is further evidence it does very little at all except block H1 receptors.
And the problem with getting the right balance of potency at the two receptors at the same time is very much like the difficulty that exists with so-called dual action antidepressants. Most of them have too great a discrepancy in their potency for the two effects (SRI vs. NRI) to be useful. The same argument would appear to apply to SGAs, even if you do believe in the benefit of blocking 2A receptors.
We seem to be besieged by “ifs and buts”.
Quetiapine D2=500, 5HT2A=700, H1=20
NorQuetiapine D2=450, 5HT2A=80, H1=3
Promethazine D2=250, 5HT2A=170, H1=1
Promazine D2=200, 5HT2A=15, H1=2
Data, as always, from the PDSP database (approximate means from several sources, not all HCR data). Usual error ranges for such assays indicate these three drugs have the same pharmacological profile are likely to be clinically indistinguishable.
Note also that both their ring structure and 3D appearance (configuration) are very similar indeed. See http://www.drugbank.ca/
Also, I find it interesting that Meltzer has apparently omitted to address the question of agonist directing trafficking at the 5-HT2-receptors, see (67, 93, 94). More on this another time.
I am not surprised to see this phrase being invoked. If anybody thinks they really know what it means please let me know, but you will probably locate the end of a rainbow first. I recommend reading Sulzer’s paper re this (95).
This commentary is not an analysis of the long-term side effects of these drugs, nor their toxicity in overdose. However, since it appears they are being marketed at least partly on the basis that they are less likely to give rise to legal actions for tardive dyskinesia in the future a few words may be appropriate.
There is no sound basis in theory (except lower equivalent dose) why these drugs should cause less tardive dyskinesia. Even if they do, which must be considered doubtful, this is probably offset by considerations related to metabolic syndrome with its concomitant life shortening complications (96-98).
The proposition that these drugs are going to turn out to have less long-term side-effects is without sound theoretical foundation or evidential basis: it represents a triumph of hope over experience.
Estimating uncommon side-effects and complications resulting from long-term treatment is fraught with methodological difficulties and pitfalls which have clearly not been overcome, as evidenced by the recent analysis of the incidence of NMS (neuroleptic malignant syndrome) by Gurrera (99).
Similar difficulties and pitfalls arise when trying to estimate the long-term incidence of tardive dyskinesia and it seems highly unlikely that any of the figures currently available, or likely to be available for the next decade or two, will be anything like accurate enough to allow comparisons of the relative risk between drugs.
These drugs illustrate in the most dramatic way possible with the awful gap between FDA approval and the establishment of long-term effect. There is not even the shadow of a proper system of post-marketing surveillance in any Western country. This means that reliable data on the longer term effect of these drugs is simply non-existent. About the only data are available in this category comes from socialist Scandinavian countries where they can establish things like eventual suicide and mortality rates with different drugs with at least some degree of reliability cf (6).
We thus have an extraordinary and largely unacknowledged scandal where chronically ill patients are acting as guinea pigs for an unregulated experiment on an unprecedented scale. This applies even more poignantly to the scandalous overuse of these drugs in depressive disorders and other off label conditions. What makes it even more pathetically incompetent and unethical is that no attempt is being made to gather the data that is accumulating as a result of this experiment. It is appropriate to illustrate that statement with a simple example. Many of these drugs cause substantial weight gain, a problem that has profound long-term health consequences. Few doctors possess accurate scales to weigh patients, and even fewer record regular measurements of weight. No central agency collates data, nor is there large-scale aggregation of data, and therefore no reliable scientific statements can be made about the propensity of these drugs can cause weight gain. It is incompetent lunacy.
The dollar value of these so-called “atypical” antipsychotic drugs is way beyond the financial imagination of most of us. The Eli Lilly drug Zyprexa (olanzapine) has been earning the company 5,000 million (yes, that is 5 billion) dollars per year for at least the last five years. That represents a substantial portion of Eli Lilly’s total sales revenue (5 out of a total of 21 billion). It is understandable that they would be keen to extend their patent and maintain that income stream.
In their 2010 Annual Eli Lilly Company Report, re Zyprexa (olanzapine) the Company state, concerning penalties imposed on them:
“Since June 2005, we have settled approximately 32,720 claims. The two primary settlements were as follows:
In 2005, we settled and paid more than 8,000 claims for approximately $700 million.In 2007, we settled and paid more than 18,000 claims for approximately $500 million.
In January 2009, we reached resolution with the Office of the U.S. Attorney for the Eastern District of Pennsylvania (EDPA), and the State Medicaid Fraud Control Units of 36 states and the District of Columbia, of an investigation related to our U.S. marketing and promotional practices with respect to Zyprexa. As part of the resolution, we pled guilty to one misdemeanor violation of the Food, Drug, and Cosmetic Act for the off-label promotion of Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia, between September 1999 and March 2001. We recorded a charge of $1.42 billion for this matter in the third quarter of 2008 and paid substantially all of this amount in 2009. As part of the settlement, we have entered into a corporate integrity agreement with the Office of Inspector General (OIG) of the U.S. Department of Health and Human Services (HHS), which requires us to maintain our compliance program and to undertake a set of defined corporate integrity obligations for five years. The agreement also provides for an independent third-party review organization to assess and report on the company’s systems, processes, policies, procedures, and practices. In October 2008, we reached a settlement with 32 states and the District of Columbia related to a multistate investigation brought under various state consumer protection laws. While there was no finding that we violated any provision of the state laws under which the investigations were conducted, we paid $62.0 million and agreed to undertake certain commitments regarding Zyprexa for a period of six years, through consent decrees filed with the settling states.”
Gosh! What jolly good chaps they are, so generous and public spirited! Nothing was any fault of theirs, of course! The corporate entity has no memory, its behaviour is psychopathy distilled to the purest essence.
Jansen make Risperdal (risperidone) which is son of haloperidol, one of the original drugs from the 1960s. That drug alone has earned them around $US 34 billion in total: they are currently (Jan 2012) being sued for 1 billion by the Texas authorities for varies alleged infringements. But they only paid 160 million, the stockholders are happy, and so it goes on and on and …
Google it, you will be busy for days. Almost all major companies have been fined huge sums for fraud. I think Pfizer’s 2.3 billion in 2009 is the single largest fine in US corporate history so far, but I doubt that record will stand for long. See e.g. http://temp.fraudpiorg.officelive.com/jjmarketing.aspx
Published payments to Doctors in the USA to promote drugs totalled $200 million in 2009. Risperdal’s star Key Opinion Leader (KOL) (Prof Biederman of Harvard, $1.6 million in payments) when asked on oath in court if there was anyone above his “rank” of “full professor” answered “God”. We could go on and on, but do you need to know any more? I do not.
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