Mirtazapine & tranylcypromine: Contrast & irony

Mirtazapine (Remeron etc.) & tranylcypromine (Parnate etc.) illustrate some marked contrasts, for instance: in price (although both are long out-of-patent), in effectiveness, in side effects, in mechanism of action, and in people’s knowledge and perceptions about them. They also illustrate how history, non-medical factors, and chance, play a major role in determining the usage of drugs. Unfortunately, pharmacological knowledge and reality often take a back seat.

Many people will be aware that out-of-patent drugs, that should be cheap (like 10 - 20c per tab) are now frequently being sold at prices way above (like 100 times higher) what can be justified by decent business or ethical considerations. I will not dwell on it here, just Google the phrase ‘outrageous price increase drug’.

The CEO of one company, who recently ‘gouged’ an arbitrary price increase of many thousand-fold, must surely be a strong contender for the ‘arsehole-of-the-year’ contest (he lost his job, it turns out he was only ‘passing through’). Here are updates: http://www.cnbc.com/2016/08/30/pharma-entrepreneur-shkreli-sells-kalobios-stake.html

http://www.forbes.com/sites/kennethdavis/2016/06/03/a-market-fix-for-generic-drug-price-gouging/ - 326c32467731

The two drugs that I am discussing here provide a number of revealing contrasts from all possible points of view, the first being in the price-hike field. The price of Parnate (tranylcypromine) has for many years been very modest since it has been out-of-patent for ages. But more recently the price has been much increased in most jurisdictions. The UK National Health Service are currently paying £248.14 for 28 x 10 mg tablets (around 700c per tab.), putting the cost of a typical month's treatment at a couple of thousand US dollars or more. Insane, obscene.

The other drug, mirtazapine, remains dirt cheap, £1.80 for 30 x 30 mg tablets, around 10c a tab, which is all it is worth. That is about 500 times cheaper! Perhaps when they learn whatever tricks the ‘Parnate people’ seem to be getting away with, it will rocket up in price also! It is very popular, I am told, so much more money to be made there! Mind you, mirtazapine should be cheap, since it is weak and there is considerable doubt that it is even an antidepressant. At least one could plausibly argue that Parnate is 500 times better and therefore it is worth more!

People may be taken-aback by the notion that ‘mirtazapine is not an antidepressant’, after all lots of people with ‘depression’ feel ‘better’ on it. On the face of it, I am talking nonsense!

Let me explain: most people who describe themselves as having depression have, or at least are aware of, mainly anxiety symptoms of various sorts. They therefore generally feel significant benefit from any drug that alleviates those symptoms, whether that be a placebo, alcohol, benzodiazepines, or other sorts of sedatives.

I have written extensively both in scientific papers (1-6) and on this website, about the outrageously dishonest evidence that was used to market mirtazapine (Remeron etc.), the links:

http://www.psychotropical.com/mirtazapine-a-paradigm-of-mediocre-science

http://www.psychotropical.com/mirtazapine-dubious-evidence

Simple fact: mirtazapine’s potency as an antihistamine is close to 1000 times higher than any other property it possesses. That indicates those other properties are irrelevant at therapeutic doses (see receptor data in above links, especially my review which is still the most complete compilation of receptor data on mirtazapine (6)).

Even its supposed main AD action on alpha-2 is at the very best 100 times less than its H1 potency, possibly closer to a 1000 times less. If action on alpha-2 receptors was one tenth of the H1 potency that would be a sufficient discrepancy to make that property of little or no clinical consequence. At one hundredth it is not even in the ball-park.

In any sane & honest world it would have been marketed as a specific antihistamine, with no other significant activity claimed! How they got away with conning the academics into accepting their story still leaves me speechless. Sadly, it suggests the ‘key opinion leaders’ who spruiked it were either carelessly ignorant, gullible, or dishonest (may be a bit of each of those). May be they had to deceive themselves before they could deceive others?

Clearly, ‘honesty’ is not a word one can use in conjunction with the marketing of drugs generally (without putting unconscionable strain on the semantic integrity of the words utilized), and that certainly includes Organon's publications about mirtazapine. I will give one quick example here, but the above links (and my peer-reviewed paper) have more details.

Mirtazapine was simply a re-badged version of mianserin (i.e. it is a close structural homologue that enabled renewal of the patent — it was initially called aza-mianserin — and is pharmacologically almost exactly the same). Mianserin was introduced in the early 1970s, and was not an effective antidepressant. Mirtazapine was claimed to be different, and of course better, by virtue of its claimed more potent antagonism at alpha adrenergic type-2 receptors, which was hypothesised to boost noradrenaline and therefore help depression. However, the truth was that Mirtazapine’s antagonist potency at alpha-2 receptors is actually less, not more, than that of mianserin (from the company’s own data, but they somehow ‘lost’ that paper)!

Furthermore, various efforts to develop similar drugs (by Organon & others) with more potent alpha-2 antagonist activity, but less sedative activity (7-11), failed, because it seems they showed neither antidepressant, nor anti-anxiety, effects. Needless to say those results were all swept under the carpet, or just not published, and it is difficult to find information about those failures. Few people now would recognise the word ‘serenic’, which was the word coined to describe some of these drugs. That is how much of a failure they were. It is difficult to find a word on which a Google search returns less hits!

You might think, as I do, that would be the last nail in the coffin for any credible notion that mirtazapine is an AD. After all, it means that mirtazapine, if it really was an AD, would have to have had some (still undiscovered) mystery property, that none of the subsequently produced ‘improved’ (but failed as ADs) drugs possessed. Not likely.

For more than 30 years now I have held the view the supposed AD efficacy of the ‘terrible twins’, mianserin and mirtazapine, was unfounded. But, like a vampire, this idea seems immortal (and just as horrible).

Dozens, possibly even hundreds, of antihistamines have been on the market over the last 60 years: not one has become established as effective antidepressant. I leave you to draw your own conclusions without even knowing about or considering the mass of crooked evidence relating to mirtazapine.This drug is just an antihistamine, which means it has anxiety reducing activity (the same as doxepin, and quetiapine, which have no true antidepressant activity either): just sedative, anxiolytic, appetite-increasing (therefore weight-increasing) antihistamine activity (12).

But, I can hear some people thinking, doesn't he know about all the double-blind trials that prove mirtazapine is an antidepressant. Let's ignore, just for the moment, the fact that there are many double-blind trials (tens of thousands of them) ‘proving’ almost everything tested in the last 50 years, from vitamin C, to St John's Wort (and innumerable other ‘botanicals’), through to an appalling mish-mash of drugs, are all antidepressants.

Allow me recap quickly, for those who do not appreciate a key aspect of the assessment of antidepressants. Almost all of the subjective & imprecise rating scales used to assess antidepressant response in drug trials are unreliable, but they are substantially affected by sleep and anxiety measurements. This means that a drug that acts as a hypnotic, sedative, anxiolytic will improve the measurements on these scales and therefore allow it to be paraded as an ‘antidepressant’. You can find a drug trial showing almost every single drug introduced in the last 50 years, with such properties, and that includes antipsychotic drugs (like quetiapine***), is an ‘antidepressant’. I think it is obvious that is meaningless.

*** For an analysis of the misconceptions surrounding antipsychotic drugs, see: http://www.psychotropical.com/atypical-anti-psychotics

It would be my contention, of course, that such drugs are not ‘proper’ Ads, precisely because they do not improve the important basic ‘core’ changes that generate the signs and symptoms that are the essence severe and serious episodes of depression. Those are: lack of drive, energy and motivation, ‘vitality’, and diminished ability to get ‘positive feedback’, satisfaction, fulfilment, pleasure and enjoyment. For more on this see: http://www.psychotropical.com/1-thinking-life-stress-and-depression

Again, we will not dwell on this here since I have written about it elsewhere. But remember, people with serious symptoms of anergia and anhedonia should not expect to get a significant ‘antidepressant’ effect from mirtazapine (or quetiapine (Seroquel)).

However, in direct and dramatic contrast to this tranylcypromine (Parnate) is a most effective, perhaps the most effective, drug for improving severe depression. Although it has no sedative effects it improves symptoms of agitation and anxiety, that are ubiquitous secondary symptoms of such illnesses, rapidly and dramatically. Such responses constitute good evidence that symptoms of severe anxiety and agitation are secondary to the core depressive illness changes of anergia and anhedonia. Because they are secondary they respond poorly to symptomatic treatment with sedatives alone, but extremely well to proper treatment of the underlying illness — with Parnate (and ECT).

Incidentally, as far as the long-term balance of harms vs. benefits is concerned, I would suspect that if good data were available it would show that mirtazapine causes more morbidity and mortality than tranylcypromine. This is by virtue of its considerable contribution to long-term weight gain, which is a frequent problem even before people start the drug.

Incidentally, contrary to what is stated in most current texts, it is perfectly safe to mix mirtazapine with tranylcypromine (Parnate).

References

1.         Gillman, PK, Amitriptyline: Dual-Action Antidepressant? J Clin Psychiatry, 2003. 64: p. 1391.

2.         Gillman, PK, Mirtazapine: unable to induce serotonin toxicity? Clin. Neuropharmacol., 2003. 26: p. 288-289.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14646604

3.         Gillman, PK, Mirtazapine: not a dual action antidepressant? Aust NZ J Psychiatry, 2004. 38(4): p. 266-7.

4.         Gillman, PK, Differences between mianserin and mirtazapine. A critique of Wikström et al. Medicinal Chemistry, 2005.

5.         Gillman, PK, A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry, 2006. 59(11): p. 1046-51.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16460699

6.         Gillman, PK, A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Hum Psychopharmacol, 2006. 21(2): p. 117-25.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16342227

7.         de Boer, T, Broekkamp, CL, Gower, A, de Graaf, JS, et al., The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha 2-adrenolytic activity. Neuropharmacology, 1988. 27(3): p. 251-60.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2897643

8.         Colgan, ST, Dumont, ML, and Ruggeri, SG, Assay and purity evaluation of sunepitron hydrochloride by reversed-phase liquid chromatography using a reference standard composite. J. Pharm. Biomed. Anal., 1998. 18(3): p. 429-40.

http://www.ncbi.nlm.nih.gov/pubmed/10096837

9.         Andrews, JS and Pinder, RM, Chemistry and pharmacology of novel antidepressants, in Antidepressants, BE Leonard, Editor. 2001, Birkhäuser Basel: Basel. p. 123-145.

10.       Gentili, F, Pigini, M, Piergentili, A, and Giannella, M, Agonists and antagonists targeting the different α2-adrenoceptor subtypes. Current topics in medicinal chemistry, 2007. 7(2): p. 163-186.

11.       Becker, OM, Dhanoa, DS, Marantz, Y, Chen, D, et al., An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J. Med. Chem., 2006. 49(11): p. 3116-35.

http://www.ncbi.nlm.nih.gov/pubmed/16722631

12.       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