Mirtazapine, a paradigm of mediocre science in a deficient regulatory environment
This essay summarises the data and that indicates much of the early work published on mirtazapine was inaccurate and misleading, and points out that there is little evidence to substantiate the idea that mirtazapine is any different form mianserin.
More recent data is reviewed that demonstrates there is unlikely to be any meaningful difference between these two drugs, and that the supposed mechanism of action making it a different from other antidepressants is probably mistaken (see table of receptor affinity data). There must be major doubts about its ability to act as an effective antidepressant because there is no established plausible mechanism by which it could achieve that effect. If it is an antidepressant, then new ideas are required to explain how it achieves this effect.
For more than a decade Mirtazapine, (aka 6-aza-mianserin) has been marketed as a drug whose mechanism of action is claimed to be different (via adrenergic alpha 2 antagonism) to all other antidepressants (including its predecessor and close structural analogue mianserin).
Structures for these can be found at these links:–
- Mirtazapine:– http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4205
- Mianserin:– http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4184
The ‘6-aza-‘ tag simply indicates that one carbon atom is replaced by a nitrogen, in the 6 position. So these two compounds are almost identical: small changes can make big differences, or no difference at all: for physicochemical data see (1).
Mirtazapine’s potency, and what effect that has on receptors or neurotransmitters, and what changes that might cause, and wether it is significantly different to mianserin, indeed whether it is an antidepressant at all, are all questions that require quality, replicated scientific evidence: but this has never existed.
Science places the onus on those making novel claims and propositions to adduce evidence to support or ‘prove’ them (prove is a repetitively misused word). This was, and still is, a novel claim because there is no established mechanism by which this drug might exert an antidepressant effect. Science also requires independent replication of evidence (remember ‘cold fusion’). There are two parts to this process, the first is replicability, that is a description of methodology sufficient for it to be precisely repeatable, the second is the actual replication and the attainment of the same result. This essential and fundamental requirement of real science has been systematically ignored in the psychiatry / psychopharmacology fraternity. There are some understandable factors that influence this, but that does not make it excusable. Most drugs are approved following consideration of data given to regulatory authorities by a single interested party, the pharmaceutical company making the drug. It is rare for independent replication of any part of this evidence to be sought, or attained. prior to approval: and, as this story reveals, afterwards either. This takes Psychiatry into a grey area where it is rubbing shoulders with alternative medicine and sustaining itself with partisan evidence and wishful thinking (2-5).
Medical scientific publishing has been subjected to vigorous criticisms as a result of appreciation of the lack of objectivity that distorts the scientific method. Comments from eminent journals create a perspective. The editor of the BMJ, stepped down in 2004, and wrote that Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies (6). Horton, the Lancet editor, stated, Journals have devolved into information laundering operations for the pharmaceutical industry (7), and Angell, the NEJM editor, said they were, primarily a marketing machine co-opting every institution that might stand in its way (8). The evidence is that even meta-analysis and practice guidelines are tainted with bias (9-13). Favourable evidence about drugs is sometimes manufactured (14-16). Antidepressant drugs are still being proved to work in trials and then found not to work by ordinary clinicians (17). See my essay Why Most New Antidepressants Are Ineffective: And How Pharmaceutical Companies Have Deceived Doctors for further discussion of the issues.
Mirtazapine is the 6-aza- analogue of mianserin, and was introduced as a new antidepressant, christened as such in the title ‘… new anti-depressant Org 3770 …’ of the first publication about it. At that juncture there was no published evidence whatsoever of its antidepressant efficacy (18). This is an extra-ordinary and outstanding example of promoting an idea before presenting any scientific evidence. Indeed, this is why author instructions in some journals specifically state that the title of an article should not announce the results. That admonition is especially relevant here, because not only did they announce the ‘result’ but also there was no data whatsoever in the article concerning antidepressant effects. As Sir Humphrey advised in an episode of ‘Yes, Minister’, ‘Always get rid of the difficult bit in the title – it does less harm there than in the text’ (19).
I have recently published a review of the human pharmacology of mirtazapine and mianserin (20) . In brief, the current research evidence fails to support a meaningful distinction between them. Their most potent property is histamine receptor H1 antagonism, which is strongly associated with sedation and weight gain (21). This seems not to be perceived as a positive sales attribute because out of 26 ‘Organon’ papers (i.e. papers that appear to be funded by the pharmaceutical company ‘Organon’, and/or written by employees) on mirtazapine this property receives brief mention in only one of them (22) . The maximum difference in Ki values at the adrenergic alpha2 (2) receptor (which is claimed to mediate its putative antidepressant actions), for mianserin / mirtazapine in the Organon papers is two fold. That is insufficient to substantiate any claimed difference, because the experimental variation in these measurements is 5-10 fold, as revealed in the PDSP online database (http://pdsp.med.unc.edu/) of receptor affinity data (23) and summarized in my review (20).
It is appropriate to pause and recap on the presentation and manipulation, as well as the meaning and relevance, of the above data. The most potent pharmacological property of this drug is barely mentioned, even though it is the most potent anti-histamine currently available on the world market. A minor, and almost certainly insignificant, difference in 2 potency is stated dogmatically, and without acceptable evidence, to explain the drugs supposed antidepressant effect. No-one in the profession appears to have seriously questioned the evidence. Indeed calling the data presented ‘evidence’ is unjustifiably agrandifying it. The full extent and nature of this distortion of the scientific process is revealed more fully in the analysis of the papers presented by Organon discussed below.
A very large number of reprints from a supplement to the Journal of Clinical Psychiatry (24) (lucrative for the journal) tabulating data on mirtazapine were purchased at substantial expense, by whom I do not know (but I am definitely not awarding a prize for the best guess), and given to huge numbers of doctors all over the English speaking world. Evidence indicates supplements are of lower standards (25) which in my opinion applies in this case. Figure 1 in this contribution (p 560, Receptor binding profile of mirtazapine) displays a bar graph of receptor affinities. This cites a single reference for the data in the graph and has no legend to indicate that it is in fact compiled from different experiments, in different species of animals, and that the work was spread over 6 years and published in several different journals. The table in the reference given (26) is itself not the original presentation of the data, it gives no original data either, but presents data adapted from 3 further references (27-29). Those three different references, for anyone who troubles to dig that deep, in turn reveal the use of various preparations including: rat cortex, vas deferens, mouse neuroblastoma, guinea pig ileum etc. The basis for these adaptions is not discussed or elaborated.
The original Figure 1 in the J Clin Psych supplement therefore produces completely misleading impressions because it makes utterly invalid comparisons. It would have been clear at that time that it was not valid or accurate to make such comparisons, between different species and different experiments in different laboratories. In my opinion, it is impossibly difficult to see how those who produced this table could be described as both competent and honest. The earlier, and only, de Boer (Organon) paper that reported values for both drugs (mianserin and mirtazapine), apparently from the same experiments (27) found that the A2 affinities were identical. That paper is no longer referred to at all, and it does not appear in the citations of the J Clinical Psychiatry article (24). There is no apparent justification for choosing to ignore this contradictory data without comment and explanation. This exercise is certainly not acceptable science, and at worst, it is disingenuous. It might be noted that this egregious piece was published in J Clinical Psychiatry, which is regarded as a prestigious and high profile journal.
My comprehensive analysis of all the more recent receptor data known, concerning mianserin and mirtazapine, was published recently (20) and highlights the lack of significant differences between these two drugs. It is important to appreciate that even using the latest human cloned receptor techniques the inter-laboratory variation in receptor affinities measured is of the order of five to 10 fold. This makes it clear that the small differences selected from the early work on mirtazapine are exceedingly unlikely to be meaningful: to assign accuracy to them would be a triumph of hope over experience.
What is known, but not known by the people who need to know what is known, is often the most important thing we need to know. And indeed there is a particular piece of information that few, if any, researchers in psychiatry will have become aware of. It is this: Organon synthesised and tested another drug with A2 antagonist properties (Org 6906) that had the potentially significant advantage of not being a potent histamine H1 receptor antagonist (30). You might ask what happened to this drug, but we do not know. Nothing further was published about it, at least nothing referenced in the NLM Pubmed data base. Obviously, if it was trialed in humans, with negative results, this information would be significant. But secrecy prevails and the advancement of knowledge counts for less.
In retrospect, it is apparent that not only has there been uncritical acceptance by academics of the evidence for the supposed action of mirtazapine, but also there has been widespread support by influential figures (dubbed ‘key opinion leaders’ in pharmaceutical company jargon), at least some of whom have been, and probably still are, in receipt of large sums of money (31). In this context one further peculiarity concerning the publication of this report is notable: the reprint attributes authorship to Hirschfeld, RM. a member of the Department of a noted key opinion leader at Brown University, whereas the pub med database makes it an anonymous contribution:–http://www.ncbi.nlm.nih.gov/
The idea that mirtazapine is a dual action NaSSA (‘noradrenergic and specific serotonergic antidepressant’) in humans continues to be widely supported by Key Opinion Leaders (KOLs) (32-42). It has no significant serotonergic effects in either humans (20) or animals (43), so this is clearly unlikely to be correct and is ‘spin doctor’ jargon, not science.
The history of the investigations concerning mianserin and mirtazapine is one of a lack of scientific rigor in data presentation and a lack of objectivity in analysing results. This may be accounted for by a predominance of commercial interest combined with lack of independent replication that has been enduringly counter-productive throughout the pharmaceutical industry. The ultimate irony is that this is driven by secrecy and the belief that each individual company may make a significant and profitable advance before others. The real outcome is revealed in the history of the last 50 years: a catalogue of complete and abject failures to find more effective antidepressants. There has been no significant advance (in efficacy) since the discovery of tranylcypromine and clomipramine.
There are many lessons to be learned from this sorry saga. It will be interesting to see what is revealed as parent company, Akzo-Nobel, sells off the subsidiary Organon, because mirtazapine is a substantial part of its revenue stream and they have worked hard to maintain that stream. Substantial damages have been paid by Organon following the USA court settlement about that.
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Pharmacological profile of mirtazapine and mianserin: uptake inhibition and receptor antagonism
Ki in nM from my previous data (44)
|Post-synaptic receptor antagonism|
The above data is now in PDSP Ki data base. Lower numbers indicate greater potency. The first six rows contain three pairs of data (a(45), b(46) , c(27)), each receptor measurements from the same laboratory. Two of these pairs (a, b) of data were discovered by me, and caused to to be entered into the PDSP database, because they were previously ‘unknown’, having been accidentally omitted from one publication (b) and in the other case published only as an abstract (a) and not noticed or quoted by anyone else.
The two notable points are:– Firstly, that the new human cloned receptor estimates of the relative adrenergic A2 potency of these drugs indicates that mianserin is actually the more potent as an A2 antagonist. This is precisely the opposite to what is required to justify the claim that they made that mirtazapine is better / different. Secondly, it highlights that there is a 5-10 fold variation in measurements between different techniques and laboratories which emphasises that the minor differences found by the pharmaceutical company Organon initially were much too small to justify any speculation that they were different.
Note that the’Organon’ results quoted above (27) are the ones that appear to have been forgotten about, and were not subsequently quoted or referred to, (e.g. other data showing a larger difference was used in the widely disseminated article in the Journal of Clinical Psychiatry). In view of that, and for the accuracy of the record, I quote the words from their own paper:–
‘The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 (i.e. mirtazapine) and mianserin with identical affinity, … . A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.’
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