Tranylcypromine (Parnate): A Brief History and a Enduring Anomaly
This note is about how tranylcypromine (TCP, Parnate) only just made it into the modern era and the extant armamentarium of drugs (1-3). This, despite the fact that it is probably the most potent antidepressant drug currently available anywhere in the world, particularly for severe endogenous and melancholic and psychotic depression types (to the extent that those may be valid sub-divisions of severe depression). Despite the lack of so-called “gold standard” double-blind-trial evidence there is much other evidence and experience to strongly support the epithet of “most potent” for TCP, about which I expound elsewhere [link].
Suffice it to say, in this context, that surveys of the opinion of patients who have suffered dreadful long-standing severe depression, and who have had many different sorts of drugs, show conclusively that they-themselves express a strong opinion that MAOIs, especially tranylcypromine, have given them more improvement (and often with less side effects) than any other treatment, including ECT (4, 5). That certainly accords with my experience: I have frequently seen long-standing remission induced by tranylcypromine (Parnate) in patients who have failed to benefit from ECT, and in those who have been continuously ill for 10 years or more, despite multiple attempts at treatment: I have published a brief summary of my retrospective audit of treatment of psychotic depression with TCP (6), and see also “anecdotes” [link].
Also see info on patient’s comments at: http://www.askapatient.com/viewrating.asp?drug=12342&name=PARNATE
It is a puzzling anachronism that, despite high patient satisfaction and the perception of superiority over other newer drugs, so few psychiatrists actually utilise MAOIs. Such meager data as exists indicates extremely poor knowledge and experience of MAOIs amongst a great majority of psychiatric specialists. Indeed something like 95% of psychiatric specialists in the western world have never used them for treatment (7-9). By any analysis of science and logic this is an incredible situation. Those who have read my writings about the biases in the literature produced by the financial power and interests of pharmaceutical companies will appreciate what is the most likely explanation.
Even the editor of the British J of Psychiatry, a conservative publication by any standard, has stated recently (10): “Most of the good old drugs have been abandoned and their replacements, all drugs still under patent, have been marketed successfully but are no better, and in some ways worse, than their abandoned predecessors.”
Tranylcypromine (Parnate) nearly ceased to be an approved drug, at least in the USA, when the DESI* initiative demanded a reappraisal of drugs in the American market in the early 60s (for details of this story see Shorter (3)).
* For info on DESI see http://en.wikipedia.org/wiki/Drug_Efficacy_Study_Implementation
FDA and Clinical Drug Trials: A Short History
Under pressure from the FDA and despite protest from SKF (Smith Kline and French Laboratories, as it then was, now part of GSK) TCP was actually withdrawn from the market in Feb 1964 (1, 11), but returned in the later part of that year. Up until then tranylcypromine had been widely recognised as being effective in severe melancholic depression, even when ECT had failed (2, 3). It was only re-admitted to the American fold of approved drugs after further “studies” (1) and with restrictive conditions and sterner warnings (11). These “studies”, as far as I can ascertain, were never published, presumably because they were merely FDA reconsiderations of pre-existing material (after all, 6 months would have been insufficient time to do new studies). It is pertinent to observe that the FDA had almost certainly bitten off more than they could chew vis-à-vis DESI. They had a lot of inexperienced staff (11) who would have been struggling to do an adequate analysis.
One of these re-approval conditions was the specific contra-indication of its use in melancholic depression, which endures in the current USA PI (12). The British did not over-dramatise these events and they never withdrew it from sale. Incidentally, when I say over-dramatise I am not being patronising or anti-American; indeed it was an American, in JAMA, who used the words “hysterical” and “ill-advised” in the context of TCP withdrawal and comments about the American response to the issue (1).
Exactly what caused this distortion of experience and logic is mostly lost in the archives and the mists of time. The AMA “Council on Drugs” summary of 1964, published in JAMA (1), is a good example of “experts” prematurely asserting their misperceived authority: indeed, their “monograph” might be considered ultracrepidarian.
The Council on Drugs members were apparently unaware of important research data (13-22), all of which they conspicuously fail to note or cite. I do not know what sort of doctors were on the AMA “Council on drugs” (we can assume they were all, or mostly, analysts by training, and apparently with a poor knowledge of pharmacology), but they missed an opportunity to develop any understanding of the difference between the tyramine reaction and serotonin toxicity. That is an important distinction that psychiatrists failed to make for decades after this and which justifies the scathing opinions I express about them (see my material and papers on ST). They certainly could have had a stab at it, if they had studied the references cited above, i.e. (13-22). Those all predated their deliberations and would have been available to them. That research was done by some rather eminent pharmacologists, one of whom was no less than the Lasker-prize-winning Bernard Brodie, whose laboratory also produced Nobel prize winners.
This AMA “Council on drugs” report is probably the (un-founded and definitely un-referenced) origin of, among other misconceptions, the idea that: “Tranylcypromine should not be administered to any patient … with cardiovascular disease [or] hypertension.”, and that it is “incompatible with general anaesthesia”, and various other, either dubious or groundless, assertions which still seriously mis-inform clinical practice.
It is also apt to note that the product information current in 2013 for Parnate from GSK continues to be a litany of mistakes, mis-understandings and misinformation (like many other standard sources on MAOIs). A number of these mistakes are sufficiently serious that, were similar errors to be committed by a physician in the care of a patient, they would probably qualify as medical malpractice. It is astonishing to me that such an error-ridden document can appear as an official representation of what is correct/advised vis-à-vis MAOIs/Parnate: it leaves me in a state of speechless bemusement. Since those comments represent robust criticisms I will briefly justify and contextify them for those who are not familiar with my work and expertise. I am a recognised world authority on serotonin toxicity/syndrome, which is one of the two possible serious drug interactions involving tranylcypromine. As such it is my opinion that the information in the PI, particularly where it is relevant to serotonin syndrome, is not only poor but also incorrect. Those are serious errors and omissions with implications of life-threatening clinical relevance. It is no trivial matter.
All this illustrates how chance events and twists of history can change both people’s perception of reality and their clinical practice.
The historical timing, and the consequences of DESI, conspired to produce the anomaly of tranylcypromine being specifically disapproved of for precisely what it was, and still is, best for, that is to say severe melancholic depression with or without delusions. The at times hysterical over-reaction to its perceived disadvantages, or as many people misleadingly expressed it, perceived “dangers”, led to it being relegated to a third-line drug, or not used at all [see “anecdotes”]. Indeed, as indicated by the above references, most practitioners simply did not use it at all. Needless to say, if you do not use it, it does not work; and if you use it only for atypical depression then that is all it works for.
Since I have become progressively less hopeful about psychiatrists’ ability use drugs knowledgably and about the available means to (re)educate them, I therefore view positively the influence of the Internet which is giving the power to non-medical people by enabling them to make decisions for themselves, especially when their medical attendants’ knowledge and objectivity has been perverted. The number of people who contact me through the website, who have already simply ordered MAOIs for themselves via the online pharmacies, might surprise some doctors. Indeed, this is sufficiently common that I now maintain a list of recommended pharmacies which people have found reliable for obtaining such drugs.
Anyone who encounters a patronising proscriptive practitioner, who is not open to discussion and evidence, and who says: “oh no, we don’t use those drugs any more, they are dangerous” (quotes close to those words have been reported to me by many correspondents), can now, if they so choose, pro-actively re-define the doctor-patient relationship and direct their own treatment. That is empowerment, that is true democracy. What is even more positive is that such consumer attitudes, pressure and actions are becoming an important driving force for changing doctors’ prescribing behaviour. That is because consumer pressure is the most important counterbalancing force to the disproportionate influence of drug company’s mis-directing of doctors knowledge and prescribing habits.
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