Summary

 

The old irreversible monoamine oxidase inhibitors (MAOIs) like tranylcypromine (Parnate) and phenelzine (Nardil) are extremely effective antidepressant and anti-anxiety drugs that have much less by way of problems, side effects and interactions than most doctors imagine. Indeed many experienced psycho-pharmacologists would regard them as the most potent antidepressants available, and as being effective often when electroconvulsive therapy (ECT) is not.

 

MAOIs can be effective in all forms of biological depression, especially severe major or endogenous depression, that includes melancholic and psychotic depression (1). Not only that, but also, MAOIs treat or improve: hypertension, migraine, narcolepsy, epilepsy, Parkinson's disease and dementia. Details about this are given in the other sections, but it is useful to briefly note here that depression, Parkinson’s disease, dementia and hypertension often occur together and tranylcypromine (TCP) improves all of those conditions; furthermore, there is reason to suppose that it also has some of the neuroprotective action that is a part of the benefit of newer MAOI drugs like Rasagiline (2, 3).

 

TCP is often better tolerated than SSRIs or other newer ADs. If it was a newly discovered drug that would be headline news.

 

The explanation for the chronic underuse of MAOIs over several decades tells us a lot about how profits, advertising and ideology contaminate the processes of good clinical science.

 

I have now completed my four major reviews relating to MAOIs: the pharmacology of MAOIs which has been published in the prestigious Journal of Clinical Psychopharmacology (4), my contribution to a book “Pharmacology of MAO-B inhibitors and the cheese reaction” (5), the most extensive and thorough review of dietary restrictions and the tyramine content of foods that has ever been done (6) and my MB review (7).

 

This commentary will discuss various practical and theoretical aspects of the use of these drugs including their clinical pharmacology, side effects and interactions (actually very few). The dietary review (and extensive 1st hand experience) indicates how few foods need to be restricted, and that almost no foods have to be completely avoided. The review sets out in detail the evidence for limiting the intake of, or avoiding, the small number of things which contain significantly elevated tyramine and can therefore occasionally precipitate blood pressure increases. That document is linked as a recommended source of information by professor Stephen Stahl on his NEI website.

 

This commentary presently has four parts, that will extend to more in due course.

 

Part 1

 

Introduction

 

The current evidence indicates that old monoamine oxidase inhibitors, tranylcypromine and phenelzine, justify retaining a more prominent position in our treatment armamentarium than they now occupy. As a scientist I recognise the potentially misleading nature of anecdotal evidence. Nevertheless, many people may be heartened to read the story below of the man who, after 20 years of unsuccessful treatment, consulted me and got better on tranylcypromine (TCP) in six weeks (see ‘Anecdotes 1’ below).

 

Doctors’ lack of MAOI knowledge and familiarity leads to apprehension and avoidance of MAOIs; this is a major factor influencing their low usage. It is undoubtedly the case that withdrawal of all advertising and promotion about them, contrasted with the immense sums spent on the promotion of newer drugs (frequently misleading or false), exacerbates the disparity (see ‘Anecdotes 2’ for a revealing ‘inside story’ about that).

 

Psychiatry does not have a good track record for using science and the scientific method, especially in relation to pharmacology. The state of many psychiatrists' knowledge about serotonin toxicity/syndrome and MAOIs exemplifies that. It is unscientific and sad that one sees frequent references, even in specialist texts, about MAOIs being “dangerous” drugs, and also much incorrect information about their properties and interactions (see section on Interactions). The activities of the advertising spin doctors have been so successful that most doctors, including specialists, now believe that the old drugs should not be used at all because they are dangerous and less effective. It is a continual source of amazement to me how far away from the truth spin can take you (see my commentary “Science and Scientific Information” which reveals more details about that). It is common for me to hear of doctors who tell patients they should not be on dangerous drugs like MAOIs, and when patients have asked for MAOI treatment they have been told, “we don’t use those drugs any more”, or dismissive comments to that effect. Such attitudes are a powerful testimony to the effect of advertising and ideology. As is so often the case, statements like that tell you more about the person making the statement than they do about the subject under discussion.

 

I have been asked many times how to open up discussion with such doctors. Unfortunately, I do not have a magic solution to this significant problem. I suppose it is helpful to understand that there are some doctors who are scientists and are therefore open to evidence and logical argument. Unfortunately there are also doctors who operate more on a belief system, akin to other belief systems, and therefore are much less open to logical argument but are more likely to be persuaded by personal revelation and anecdote. How to achieve personal revelation with such persons is not something I claim any great insight into. For those that have the choice, when faced with such a dilemma, the obvious course of action is to seek a doctor who is open to evidence and discussion.

 

As a contribution to breaking the ice, I have in the past written letters to doctors on behalf of people and the link below is an example of such a letter, which you may download and give to your doctor.

 

http://www.psychotropical.info/index.php/anti-depressants/99-maois/206-open-letter-using-monoamine-oxidase-inhibitor-maoi-drugs

 

A Little History

 

A little history goes a long way:

 

"Progress, far from consisting in change, depends on retentiveness. ... Those who cannot remember the past are condemned to repeat it." Santayana (8).

 

The monoamine oxidase inhibitors can be considered as the first real and effective antidepressants. I discovered the earliest report of serotonin syndrome which occurred in a doctor being treated for tuberculosis in 1955 with the then ‘experimental’ MAOI drug iproniazid (9). During the 1950s the antidepressant properties of drugs with this type of chemical structure were recognised  (hydrazine rocket fuel- there was a bit of a stockpile around 1945, thankfully the manufacturers failed to successfully export their full production) and it was discovered that they acted by blocking (antagonizing) the enzyme MAO (3, 10-12).

 

As early as 1952 doctors were experimenting with hydrazines in mental disorders (13-17).

 

By 1959 iproniazid was on the market as an ‘antidepressant’, that term was first used about then (18, 19). It was closely followed (1960) by tranylcypromine (Parnate) (19-21). The Lopez-Munoz history of these events is informative reading (22, 23). See also (24-27).

 

This is also an appropriate point at which to relate how some useful psychotropic drugs did not make it into the modern era, or only just made it. That was because of the struggles involving the power and ideology of the nascent “Federal Drugs Administration” (FDA). This is an important story to be aware of, and for those interested in learning from history I recommend Shorter’s book “Before Prozac: the troubled history of mood disorders in psychiatry”; Ed Shorter is the professor in medical history at Toronto, and is an eminent medical historian (28, 29). Understanding the machinations and politics behind all of this FDA related stuff is instructive. It helps one to appreciate that whether most drugs do, or do not, get on the market sometimes has little to do with science. It often has to do with vested interests in society, business and politics. Another text that I highly recommend for those wishing to understand the (two-way) interactions between science and society is the short and pithy book by Professor Richard Lewontin entitled “Biology as Ideology” (30), and see also my commentary “Science and Scientific Information”.

 

Early Influence of FDA

 

As part of a power struggle in the early years of the expansion of the FDA in the 1960s there was an initiative called ‘DESI’. This stands for “drug efficacy study implementation”. It was part of a retrospective evaluation of the effectiveness of drugs that existed in America and had been approved prior to 1962. As part of this many psychotropic drugs required new evidence of effectiveness to be to submitted. Some were removed from the market, even Parnate was removed for short time in 1964. It was only because SKF (now GSK) did a few further studies that Parnate is now on the market at all.

 

This coincided with the recognition of the morbidity and mortality caused by the cheese effect. At that time, early 1960s, the presence of tyramine in some foods, and its effect on elevating blood pressure, was not appreciated. It is not difficult to understand how, with this background, many doctors were apprehensive about these drugs. However, it was obvious to many experienced specialists that they produced a spectacular effect in serious cases of depression which had previously been untreatable, except by ECT. One of the great ironies is, at that time, Parnate was considered especially effective for psychotic depression (I agree, see (31)). However, the new labeling, post-DESI, specifically excluded its use for that indication and relegated it to the treatment of so-called atypical depression. At this time the tricyclic antidepressants were also coming into use and had none of these perceived problematic effects. Perhaps the final death-blow was a drug trial done by the Medical Research Council (MRC) in 1965 comparing imipramine with phenelzine (32). In my opinion the dose of phenelzine was rather low, but the result was that phenelzine (and hence by association other MAOIs) came out badly, that is as less effective than imipramine, and from then on MAOIs were pretty much history in general psychiatry. However, it is striking that most psycho-pharmacologists who specialized in treating serious depression went on using them extensively. This is a prominent example of a phenomenon that is frequently encountered. Double-blind trials that are supposed to be better and more objective science than clinical observation frequently produce results which experience show to be clearly wrong. This trial was the death knell of MAOIs and yet after 30 years experience using them I would stake both my own life and my pension fund on the fact that they work very well.

 

By the mid-1980s in USA, tranylcypromine and phenelzine together accounted for more than 90% of the market in MAOIs (24).

 

The Present

 

That pretty much brings us up to the present with MAOIs, because throughout the decades of the latter part of the 20th century the number of older doctors (that now includes me!) with practical experience of these drugs gradually diminished and the new generation of doctors were inculcated with the supposed virtues and safety of the various newer drugs. Also, the MAOIs were long out of patent and furthermore the general level of interest was low, so the amount of basic research done concerning them was also low.

 

As you can read elsewhere on my website, the situation is not so straightforward, and it turns out that the information about many of these new drugs is either of poor scientific quality, or unrepresentative of the totality of work that was actually done (lost research, the file drawer effect), or just plain misleading. My interpretation of substantial amounts of that research is that it is difficult to understand or explain it, except from the viewpoint that most of it, not just some of it, was deliberately deceitful in its design, execution and presentation. The evidence that deceit is the main explanation is now extensive and convincing, as various of the commentaries on my web site document.

 

Moclobemide, Selegiline, Rasagiline and Ladostigil

 

Attempts to develop other MAOIs for depression have not been notably successful.

 

Moclobemide (selective reversible MAO-A inhibitor) is weak, if it is an antidepressant at all. My personal experience of using it, even in doses of 2,400 mg daily (which made it very expensive indeed), was that it was ineffective, and that it was in no way comparable to tranylcypromine. The work on Moclobemide constitutes another chapter in the saga of poorly carried out and dubious research, at both the experimental and clinical level (cf. commentary on mirtazapine).

 

The slightly selective irreversible MAO-B inhibitor selegiline, and most recently (more selective, about x 60) rasagiline, cannot be expected to be as potent. Inhibiting MAO-B alone does not help depression much, nor does it raise dopamine much either. Monoamines are metabolised relatively non-selectively and blocking just MAO-B may elevate dopamine a little, but not nearly as much as blocking both MAO-A&B at the same time, which is what tranylcypromine does (see below).

 

An interesting drug is ladostigil (33-36) which is just starting human trials as I write this (Oct 2011) see:

 

http://clinicaltrials.gov/ct2/show/NCT01429623

 

Ladostigil may be the first brain-selective MAO-AB-inhibitor and seems to have little inhibition of systemic MAO. That could be a major advance if those properties are maintained in real world use. One remotely possible disadvantage of this drug as an antidepressant is that it acts to increase levels of acetylcholine, which might tend to worsen, rather than improve, depression. Time will tell.

 

 

 

 

 

References

 

 

 

1.                  Wimbiscus, M, Kostenko, O, and Malone, D, MAO inhibitors: risks, benefits, and lore. Cleve. Clin. J. Med., 2010. 77(12): p. 859-82.

 

2.                  Rascol, O, Fitzer-Attas, CJ, Hauser, R, Jankovic, J, et al., A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol, 2011. 10(5): p. 415-23.

 

3.                  Finberg, JP and Youdim, MB, Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. Neuropharmacology, 2002. 43(7): p. 1110-8.

 

4.                  Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.

 

5.                  Finberg, J and Gillman, P, Pharmacology of MAO-B inhibitors and the cheese reaction, in Int. Rev. Neurobiol., M Youdim and P Riederer, Editors. 2011, Elsevier Inc. Academic Press.: Burlington. p. 169-190.

 

6.                  Gillman, PK, Monoamine oxidase inhibitors, dietary tyramine and drug interactions (V2.2.1).

 

7.                  Gillman, PK, CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol (Oxf), 2011. 25(3): p. 429-3.

 

8.                  Santayana, G, The Life of Reason. 1905: http://www.gutenberg.org/catalog/world/readfile?fk_files=1498120.

 

9.                  Mitchell, RS, Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med, 1955. 42: p. 417-424.

 

10.               Zeller, EA and Barsky, J, In vivo inhibition of liver and brain monoamine oxidase by 1-Isonicotinyl-2-isopropyl hydrazine. Proc. Soc. Exp. Biol. Med., 1952. 81(2): p. 459-61.

 

11.               Chessin, M, Kramer, ER, and Scott, CC, Modifications of the pharmacology of reserpine and serotonin by iproniazid. J Pharmacol Exp Ther, 1957. 119(4): p. 453-60.

 

12.               Selikoff, IJ, Robitzek, EH, and Ornstein, GG, Treatment of pulmonary tuberculosis with hydrazide derivatives of isonicotinic acid. J Am Med Assoc, 1952. 150(10): p. 973-80.

 

13.               Delay, J, Laine, B, and Buisson, JF, Anxiety and depressive states treated with isonicotinyl hydrazide (isoniazid). Arch Neurol Psychiatry, 1952. 70: p. 317–324.

 

14.               Delay, J, Laine, B, and Buisson, JF, [The action of isonicotinyl-hydrazide used in the treatment of depressive states.]. Ann. Med. Psychol. (Paris). 1952. 110(2:5): p. 689-92.

 

15.               Smith, JA, The use of the isopropyl derivative of isonicotinylhydrazine (marsilid) in the treatment of mental disease; a preliminary report. Am Pract Dig Treat, 1953. 4(8): p. 519-20.

 

16.               Salzer, HM and Lurie, ML, Anxiety and depressive states treated with isonicotinyl hydrazide (isoniazid). AMA Arch Neurol Psychiatry, 1953. 70(3): p. 317-24.

 

17.               Kamman, GR, Freeman, JG, and Lucero, RJ, The effect of 1-isonicotynl 2-isopropyl hydrazide (IIH) on the behavior of long-term mental patients. J. Nerv. Ment. Dis., 1953. 118(5): p. 391-407.

 

18.               Loomer, HP, Saunders, IC, and Kline, NS, A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatry Res Rep Am Psychiatry Ass, 1958. 8: p. 129–141.

 

19.               Maass, AR and Nimmo, MJ, A new inhibitor of serotonin metabolism. Nature, 1959. 184(Suppl 8): p. 547-8.

 

20.               Tedeschi, RE, Tedeschi, DH, Ames, PL, Cook, L, et al., Some pharmacological observations on tranylcypromine (SKF trans-385), a potent inhibitor of monoamine oxidase. Proc. Soc. Exp. Biol. Med., 1959. 102: p. 380-1.

 

21.               Petersen, MC and Brayer, JW, Treatment of affective depression with trans-dl-phenylcyclopropylamine hydrochloride; a preliminary report. Am J Psychiatry, 1959. 116(1): p. 67-8.

 

22.               Lopez-Munoz, F and Alamo, C, Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr. Pharm. Des., 2009. 15(14): p. 1563-86.

 

23.               Lopez-Munoz, F, Alamo, C, Juckel, G, and Assion, HJ, Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors. J Clin Psychopharmacol, 2007. 27(6): p. 555-9.

 

24.               Ayd, FJ, Jr., Invited ACNP Lecture. The early history of modern psychopharmacology. Neuropsychopharmacology, 1991. 5(2): p. 71-84.

 

25.               Ban, TA, Pharmacotherapy of depression: a historical analysis. J Neural Transm, 2001. 108(6): p. 707-16.

 

26.               Sandler, M, Monoamine Oxidase Inhibitors in Depression: History and Mythology. J Psychopharmacol, 1990. 4: p. 136-139.

 

27.               Healy, D, The history of psychopharmacology and the CINP as told in autobiography http://cinp.org/fileadmin/documents/history/books/VOL4_opt.pdf, 2004.

 

28.               Shorter, E, Before prozac: the troubled history of mood disorders in psychiatry. 2009: Oxford University Press.

 

29.               Tyrer, P, Twisted science, regulation, and molecules. Lancet, 2009. 373: p. 1513-1514.

 

30.               Lewontin, RC, Biology as Ideology. The Doctrine of DNA. 1991: HarperCollins.

 

31.               Gillman, PK, Psychotic depression and ‘multi-aminergic’ treatment strategies. Br J Psychiatry, 2006: p. http://bjp.rcpsych.org/content/188/5/410/reply#bjprcpsych_el_1100?sid=e57661d4-3fd6-4436-bbfd-0d5ac2e686a2.

 

32.               Thiery, M, Clinical Trial of the Treatment of Depressive Illness. Report to the Medical Research Council by Its Clinical Psychiatry Committee. Br. Med. J., 1965. 1(5439): p. 881-6.

 

33.               Youdim, MB and Weinstock, M, Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol, 2001. 21(6): p. 555-73.

 

34.               Weinreb, O, Amit, T, Bar-Am, O, Yogev-Falach, M, et al., The neuroprotective mechanism of action of the multimodal drug ladostigil. Front. Biosci., 2008. 13: p. 5131-7.

 

35.               Bar-Am, O, Weinreb, O, Amit, T, and Youdim, MB, The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats. J. Mol. Neurosci., 2009. 37(2): p. 135-45.

 

36.               Weinreb, OR, Amit, TJ, Bar-Am, OK, and Youdim, MB, Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. Curr Drug Targets, 2012.

 

 

 

 

 

 

The Nature of Scientific Evidence

The questions that I get asked via the website indicate that some information and discussion concerning the nature of scientific evidence and how to acquire it will be generally useful. The pursuit of scientific truth is a noble endeavour, but it is beset by the human foibles that affect all the areas of our lives. Elsewhere I have recommended the excellent book by Lewontin called “Biology as Ideology” {literal}{Lewontin, 1991 #9171}{/literal} which sets out, inter alia, the misconceptions and myths surrounding the human genome project. Lewontin mounts a powerful argument that the dominant social and economic forces in society determine what scientists do and how they do it. Stephen Jay Gould described Lewontin as “the most brilliant scientist I know” and said that his work embodies the very best in genetics, particularly in the way it debunks the reductionism of genetic determinism. That phrase 'the reductionism of genetic determinism' means, for those not familiar with the language of logic and medicine, the overly simple idea that your genes determine what happens to you. It's very important, because most of the genetic tests, now being offered directly to the public in the USA today, are of limited use. Indeed, most are, for all practical purposes, useless. The assumptions underlying them are reductionist and deterministic in a way which invalidates them. That is why most genetic tests for the way you metabolise drugs are uneconomic, unreliable, and a waste of time and money.

Science: a work in progress

Science is about ongoing investigation; it has always been, and will always be, a work in progress. Almost nothing is right or wrong, or ‘proved’. Whenever you see the word proved being used in science a red flashing light should come on in your mind. If you find an example of it in my writing let me know, because I should almost certainly expunge it.

Science tries to make increasingly accurate representations of, and predictions about, the world, as interpreted by the observations that we are able to make, imperfect as those may be. The group of people that are now generally regarded as cranks, and called the “flat-earthers” are only wrong in a limited sense. We all operate on the assumption that the earth is flat for most of our everyday activities. The block of land on which a house rests, and its construction, operate on the flat-earth principles. We do not take into account the curvature of the earth. It is only when considering things on a larger scale that the curvature of the earth becomes important.

Medical science is a difficult enterprise. I am often critical of the science in medicine, and in psychiatry in particular. That it often reflects (among other things) the enormous difficulties of research in the medical sciences which are so dependent on variables and parameters that are difficult to assess and measure.

Accessing Scientific Information

It is now easier for non-medical and non-scientific people to access scientific information. This may come in many forms, from information on educational and government websites through to scientific papers that may be available free on the Internet. Many scientific journals require payment for reprints of articles (usually $25-40 per item, even if it is only a short letter), an increasing number of papers are free, and some journals make selected papers available free because they perceive it to be in their interests. For instance, my review of the anti-migraine drugs (triptans) and their ability to precipitate serotonin toxicity was published a year or so ago, and has just been made freely available on the journal website. The stated reason is because it is a frequently highly downloaded paper. I would like to believe that is true.

Wikipedia is often a useful source of information, even though it must not be regarded as gospel. Below are a couple of links demonstrating how much effort is going in to coordinating information about open access publishing in science. In this connection one must also mention the open access journal called on the Internet called PLoS Medicine (PLoS= Public Library of Science) which was founded by several influential people, including Nobel prize winners.

http://en.wikipedia.org/wiki/List_of_open-access_journals

http://www.freemedicaljournals.com/index.htm

Two sources of information concerning papers published in the peer-reviewed scientific journals are particularly helpful. The first is the National library of medicine database that is freely available to anyone worldwide. This database registers an enormous number of scientific journals in the medical and biological sciences (but not things like geology and astronomy etc). It is possible to go on to that website and search using all of the details that one would normally expect in a database: by that I mean of the year, volume, page number, keywords, journal names, words in the abstract etc.

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

It does not take much imagination and enterprise to learn how to find quite a lot of information. However, it is well worth remembering that even sophisticated searches on such databases, performed by experienced librarians, can only be expected to find about half the relevant information that exists. That means that if somebody does a search for serotonin toxicity on such a database, and then compares what they have found with an expert such as myself, they will find I have about twice as many references. It also means that if somebody does a search for my papers they have to be a little bit careful, because my initials are PK, but I use my middle name, Ken. The inflexibility of many of the journal websites, in relation to entering your details as the author of a paper, mean that kind of irregularity is not coped with very well. As a result of this my name appears in various different ways in the database, meaning you have to search for Gillman, K Gillman P Gilman PK etc. Then of course also you find papers by people who aren't actually me. That is because, unfortunately this system still has no unique identifier for authors.

The second database that has been more recently available is Google scholar. If you look at the various subsections of Google you will find a special section ‘Google scholar’ which is an invaluable resource and covers many scientific journals not included in the NLM database.

Bibliography databases

Organising and accessing large numbers of scientific studies is much facilitated by using a dedicated bibliography database. I could not manage without one. There are various commercial ones available (I use 'Endnote'), and a Google search will soon show the variety available. Such tools allow one to interact easily and seamlessly with databases such as the NLM, and to store and organise information. (That means less fiddling around with cutting and pasting information into fields, because it’s all done automatically. A great help with my bad neck). For those who use Firefox as a browser there is a fantastic add-on called Zotero, which is free and performs as much, and more, compared to be commercially available dedicated bibliographic databases like endnote. Downloaded references come complete with an abstract of the paper (if one exists) which by itself often contains valuable information which allows assessment of the likely value of the paper concerned. Other information provided includes the authors address and affiliations, allowing direct contact with the author, which means you can request a copy of the paper if needed. However, a note on strategy is relevant here. I think the journals, mostly owned by big international companies like Walters Kluwer, Elseiver etc, are beginning to get less than straightforward. Author contact information is not always so easily visible as it used to be (and should be). Obviously there is a major financial advantage to them if you pay $25 - $40 to them to get a copy of the reprint, rather than write to the author directly, who can usually supply you with a free copy. I do suspect that publishers are too fat and too greedy and getting an unduely large a slice of the pie in relation to scientific publishing revenue. You only have to look at the share value and expansion of some of these companies to appreciate my point. Perhaps my retirement fund would be a little larger if I had purchased some of their shares long ago.

These financial considerations are having substantial impact on research, especially independent research done by people like me. Obviously I can't afford to buy reprints at $30 a copy, especially when 99/100 of them will, on reading thoroughly, prove to be of no use. That would mean I would be paying roughly $3000 for every useful paper that I find. Even major university libraries are having to cut back on the number of different journals and databases they subscribe to because of the cost.

Nevertheless, going to the journal website and looking carefully usually gives the result (author address), if the address is not registered in the NLM database. If all of that fails the NLM database will produce a list of all other papers by the same author at the click of a mouse. It is usually possible to find a different recent paper with an address. Failing that, go to the institution website of one or more of the authors of the paper and it is usually possible to find an e-mail address.

Lastly, one can always have a guess at the e-mail address because many organisations ask people to format their e-mail address in a standard way. So if you know their name & initials you can guess their e-mail address. In the past I've formatted half a dozen different e-mails addresses in slightly different ways to discover which one works. Tedious, but where there is a will, there is a way!

If anybody else has got any other clever techniques they know of in relation to this let me know, I will add them to this commentary.

Assessing the Quality of Information

It is also useful to have some idea of how to assess the likely quality of the information that you are accessing. Things posted on the Internet, like the document you’re reading now, that have not been published in a peer-reviewed journal or other source of quality-controlled information, may have 1001 hidden agendas, biases, inaccuracies and downright lies and misrepresentations. This is why so-called “peer-reviewed” journals are generally accorded higher credibility, sadly not always justified.

Peer Review and ‘Refereeing’

The term peer-reviewed refers to the filtering processes that scientific work usually has to go through before it is accepted for publication in a reputable journal (this does not generally apply to books). When a scientific article is submitted to the editor of the Journal for consideration of publication the editor sends it to 2 or 3, sometimes even more, experts in the area of study concerned. They comment on it, and recommend to the editor whether or not it should be published. Almost always, if it is recommended for consideration of publication, this will be only after amendments and revisions in response to the comments that the referees will have made. I act as a referee for journals and have a modest amount of experience with this process. This process is far from perfect, but is important as a quality control mechanism for what is published. Nevertheless it is extremely important from readers to appreciate that just because something is published does not necessarily mean it’s good true or reliable. I will not enter into a diatribe about the imperfections of the peer review system. One only has to do a Google search about peer review to see that many eminent people have various criticisms of the process, many of which I heartily agree with. The selection of referees to do peer review for journals is pretty haphazard, even for supposedly prestigious journals. I am quite sure that many editors are under pressure to get papers published quickly, and because everybody is so busy now the number of researchers prepared to donate their time for nothing to undertake the time-consuming (and usually thankless) process of criticising papers is limited. I get all sorts of strange e-mails from editors requesting me to peer-review papers that I am quite clearly not qualified or competent to do. Since the most basic research and knowledge, on their part, should have informed those editors that I am not qualified it is obvious that the system is seriously flawed. Unfortunately, although I refuse all offered assignments for which I'm not qualified, that is clearly not the case for everyone. Obviously being asked to be a referee is quite an ego boost for many people and their own subjective judgement about whether they are sufficiently expert to referee a particular topic might well be the disputed by others.

Another example, which may give a little insight into the vagaries of the system maybe useful. Unless the paper that one has submitted is rejected outright by the journal concerned, the authors are sent comments from the various referees, often two or three, and asked to amend their paper explaining precisely how they have addressed the criticisms raised by the referees. Often there are useful comments, correction of errors and suggestions for addition of important references and material. However, equally often there are comments that are less than perspicacious. Most academics are busy and need to pay attention to the number and prestige of the papers they get published in scientific journals. Often their chance of getting research grant money etc. is crucially dependent on getting good papers published in good journals. That means most of them will bend over backwards to placate referees, to the point of being obsequious, rather than argue a point, waste precious time, and risk having the editor lose patience and reject the paper. That leads to unsatisfactory outcomes. Perhaps those explanations will give some small insight into the difficulties and weaknesses of the peer review system. Nevertheless it seems to be the best we have at the moment, although I am sure it can, and should be, improved on. Time will tell.

Meanwhile it is important to understand that even articles published in the most prestigious peer-reviewed journals (which have their fair share of bad refereeing ) cannot, and should not, be accepted without criticism and reservation. Further elaboration concerning the biases in scientific publishing can be found in my essay on ‘Why antidepressants are ineffective and how drug companies have deceived us’.

Internet searches

Generally speaking unrefined searches on the Internet for medical information will lead to so much bad and biased misinformation that most people will not be able to see the wood for the trees. One has a certain sympathy for ordinary family doctors who are bombarded with questions provoked by information acquired on the Internet. My advice is this: start off by limiting your search to educational establishments, government websites, and ‘no-profit’ organisations. It is easy to do this by using the Google search feature that finds only certain suffixes, such as '.edu' or .org or .gov (enter e.g.- 'site:.edu')

It is also possible to search for particular file types, such as Adobe PDF files etc. Generally speaking people who post quality material on government and educational websites are most likely to do it in the form of PDF files rather than word-processing documents. Therefore limiting your search to PDF files is likely to produce a more refined and useful subset of results.

Remember that in many instances someone else will have done the work already for you, it's just a question of finding it. So for instance, if one was trying to find out quality information concerning diet, exercise, weight and the health implications relating to heart disease, stroke, diabetes etc. one could start by searching for the recommendations and guidelines produced by the multitude of organisations and agencies with a finger in that pie. If your search has been limited to educational sites (.edu) then you will largely avoid blatantly partisan information produced by interested parties such as those who sell beef, cheese or sugar. From those documents it is possible to learn and extract the key terms and phrases that are used in that field, and note the prominent researchers that are quoted frequently in the bibliographies of such reports. One can then put those names into the appropriate databases to find whatever else they may have published more recently.

e.g.

Google web search for heart/cardiac info, enter:-

filetype:pdf site:.edu cardiac guideline

Which leads, along with much else, straight to a paper “Conflicts of Interest in Cardiovascular Clinical Practice Guidelines” (free pdf available!)

(www.bioethics.upenn.edu/documents/COICardio-ArchIntMed.pdf )

That paper contains a list of most of the significant guidelines produced recently. All done in a matter of less than a minute.

Then put the title into Google scholar and you get the result

“Conflicts of interest in cardiovascular clinical practice guidelines. TB Mendelson, M Meltzer, EG Campbell… - Archives of internal …, 2011 - ncbi.nlm.nih.gov
BACKGROUND: Clinical practice guidelines (CPGs) serve as standards of care in practice, quality improvement, and reimbursement. The extent of conflicts of interest (COIs) in cardiology guideline production has not been well studied. Herein, we describe the scope of COIs in CPGs. ...
Cited by 4

Click on ‘cited by 4’ and you get a list of subsequent papers.

I think that illustrates my point, and the process.

That illustrates the tactic I call a “forwards search”. If you put the name of a particular prestigious or recommended research paper into Google scholar you will notice that it tells you how many other papers have cited that paper, i.e. how many papers have used it as a reference in their bibliography. If you click on that it will list all of those papers. In other words you are looking forwards in time, from the publication you put in, to see who was subsequently used it. That can be a very valuable way of finding good and useful papers that are more recent.

Depression: What Is It? Why Drug Treatment?

A great deal has been written on the subject of defining the medical illness of depression. That is not a main theme of this website, nor do I profess to be an expert in the classifying of diseases (nosology). But it is a frequently asked question, so what I will do here is to make some comments and direct readers to quality sources that address such questions.

For more than 100 years comments have appeared in the medical literature bemoaning the fact that the every-day-word used for being ‘down’ mentally is the same as the medical illness of depression. In 1906 there was an article in the ‘Journal of Mental Science’ (1) suggesting that it should not, as it was then, be called 'melancholia', because that was the word (then) in everyday 'non-medical’ use for feeling down, but rather it should be called 'depression'.

Things do not change much, we are now doing the reverse and talking of re-introducing melancholia!

That does not matter much because here what we are interested in is the optimal use of drugs (and other treatments like ECT) to treat that portion of people suffering, and sometimes dying from, this condition who will benefit from drugs. Although there is some difficulty in defining what separates the universal human experience of distress and dejection from depression as a medical illness, we can still be confident that there is such an entity as the medical illness of depression, resulting from biological and physical causes.

The ability of doctors to separate drug responsive illnesses from other conditions is still as much of an art as it is a science. There is little doubt that many people treated with so-called antidepressant drugs do not suffer from a depressive illness of the sort that is most appropriately treated by medication. On the other hand we know, despite education efforts over the last few decades, that there are still many who suffer serious drug-treatable depression but who do not get effective drug treatment.

That is the great paradox of depressive illness, that it is both over-diagnosed and under-treated. That can be explained partly by the fact that the illness is difficult to define because none of the symptoms is really patho-gnomonic (i.e. exclusively characteristic of). There are many symptoms, and the symptoms displayed differ significantly from one patient to another (i.e. it has pleio-morphic, or many-faceted, presentation).

There are several definite good reasons for being very confident that depressive illness does indeed result from both physical and chemical alterations in the way the brain works.

1.     Its occurrence, and the form it takes, is significantly influenced by an individual’s genetic make up.

2.     It occurs with substantially increased frequency in association with certain specific diseases, such as Parkinson’s disease and Cushing’s syndrome.

3.     It is precipitated (and relieved) by specific drugs, the first of these to be observed was reserpine, but there are others including tetrabenazine.

4.     It can be emulated and relieved by damage to, or electrical stimulation of, particular pathways in the brain.

Those observations are reliable and reproducible and lead to the reasonable supposition that the reverse is also likely to be true; i.e. that both drugs, and other treatments like ECT, psychosurgery, brain stimulation, may be effective, as indeed they are.

However, the simplistic the notion that seemed to gain a great deal of currency in the last couple of decades, that depression is due to a deficiency of serotonin, is clearly not quite the answer. Despite what has been written in the scientific literature there has never been much good evidence to support that. That impression was fostered through the influence of pharmaceutical companies seeking to promote the rationalization and legitimization of the supposed effectiveness of SSRIs like Prozac. In defence of psycho-pharmacologists, I would note that few that I knew ever found the serotonin deficiency theory satifactory.

Let me just add a brief word of explanation here, because I am sure there are people reading this who are thinking it is wrong because they know they have felt mentally improved after taking SSRIs. I do not dispute that, I am sure that SSRIs have a beneficial effect on mental state of many people. However that does not make them antidepressant drugs. Indeed, they were initially developed as anxiety relieving drugs. They were marketed as antidepressants to distance them from the negative impact being associated with habit-forming drugs like barbiturates and Librium/Valium etc.

Before we move on to try to illuminate what the features predictive of drug treatable depression are, it is first appropriate to comment on the American “Diagnostic and Statistical Manual of Mental Disorders”, otherwise referred to as DSM. I include myself amongst the many psychiatrists and researchers who have grave reservations about DSM and especially the way it diagnoses depression (2). It has probably served to blurr the distinction between drug treatable depression and other forms of depression, which in turn has had a significant influence on the types of patients who have been included in drug trials, and has thereby clouded the issue of drug responsiveness (3).

Updating note (2014): since I originally wrote the initial version of this commentary, quite some time ago, that discontent about DSM has grown greater and greater.

The terms endogenous, biological, melancholic, psychotic, and  atypical are used to describe those forms of depressive illness which are likely to be drug responsive. Ultimately, the most decisive demonstration of whether someone has such an illness is a definite improvement within a short time of initiating drug treatment. Although that is slightly circular logic it is nevertheless useful and worth remembering. In general medicine any definite response to a treatment with specific indications is used to presumptively confirm a diagnosis; e.g. a rapid response to an anti-biotic confirms it is a bacterial infection and not a virus. Conversely, a failure of such treatment raises a suspicion that the initial diagnosis was incorrect. That is classic Bayesian logic in operation.

Other predictors include a genetic susceptibility, as revealed by a definite family history in close family members (mother, father, brother, sister). Next come typical symptoms and signs that separate, to a greater or lesser degree, such types of depression from other conditions.

There is a description of the core changes that are the key to distinguish biological illnesses on this website in the following [links] and there are also descriptive quotations from sources in the general literature [Kay Redfield Jamison, John Stuart Mill and William Styron]. Read them; many people find they are helpful in conveying the essence of the illness.

Next, I would direct readers to the useful comments in a very recent editorial in the journal “Bipolar Disorders” (3), which is available free as an online PDF file downloaded directly with this link

http://onlinelibrary.wiley.com/doi/10.1111/j.1399-5618.2011.00972.x/pdf

Updating note (2014): Well well, no great surprise here. On checking this link I find the publishers are no longer making it available without payment.

I quote from it re melancholic features:

“Clinical features: depressed mood, persistent, lassitude; felt spiritual abandonment, attitude of depletion; hopelessness, morbid preoccupation; thoughts of perdition ⁄ ruin, anxiety ⁄ panic; middle insomnia, diurnal variation, worse in am; threatening illusions, pervasive anhedonia; loss of usually rewarding solace, wish for release (passively suicidal), paucity of thoughts; psychomotor retardation, non-precipitated mood; perplexity, distinct quality of mood, non-reactive mood, loss of appetite; drained of energy, contesting worth of or whether deserving of treatment, querulous suspicion; hypochondriasis, ambivalent morbid catastrophizing, frozen emotions; suicidal planning, pain complaints; self devaluation, unfamiliar, pathological mood; pathological guilt.”

One excellent concise source of information and well-informed discussion is the material on the “Black Dog Institute” website. http://www.blackdoginstitute.org.au/index.cfm

Needless to say there are other sources scattered widely over the Internet. The Black Dog is the best single site that I know of for depression information. Bookmark it, use it.

It is the domain of an eminent urbane polymath Australian professor, Gordon Parker, who is a leading researcher and long-time advocate of the importance of making these distinctions. The following are direct links that will download the relevant free PDFs for you with concise definitions of causes, symptoms and types of depression, including atypical and melancholic depression.

Causes of depressionhttp://www.blackdoginstitute.org.au/docs/Causesofdepression.pdf

Symptoms of depressionhttp://www.blackdoginstitute.org.au/docs/Symptomsofdepression.pdf

Types of depression (including atypical depression)

http://www.blackdoginstitute.org.au/docs/TypesofDepression.pdf

Melancholic Depressionhttp://www.blackdoginstitute.org.au/docs/AboutMelancholicDepression.pdf

References

1.        Drapes, T, A Note on Psychiatric Terminology and Classification. BJP, 1906. 52: p. 75-84.

2.        Parker, G, Fink, M, Shorter, E, Taylor, MA, et al., Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am J Psychiatry, 2010. 167(7): p. 745-7.

3.        Carroll, BJ, Bringing back melancholia. Bipolar Disord, 2012. 14(1): p. 1-5.

The TCAs: Introduction

The tricyclic antidepressants TCAs are a group of drugs of similar structure (hence their tag of TCA, which refers to their arrangement in three-rings), but they are markedly heterogeneous in terms of their pharmacological actions. Some of them can be considered as mis-classified in that they are not actually antidepressants at all. They therefore illustrate that although the structural similarity of drugs may be close, their pharmacological actions can be very different. For instance, clomipramine is a close structural analogue of chlorpromazine, but their effects could hardly be more different. See clomipramine:

http://www.drugbank.ca/structures/structures/small_molecule_drugs/DB01242

and chlorpromazine:

http://www.drugbank.ca/structures/structures/small_molecule_drugs/DB00477

Any discussion that generalises by saying 'the tricyclics ...' is certain to be unhelpful and equally certain to be inaccurate (e.g. see the appalling APA textbook chapter on TCAs about which I have commented [link]). See also my seminal review paper about the TCAs (1). [link]

When they were introduced in the early 1960s these drugs were labelled as either anti-histamines, or anti-depressants (according to how their properties were then perceived), some were mis-classified (e.g. doxepin should have been classified as an anti-histamine, and chlorpheniramine as an anti-depressant). Some readers may realise than in fact doxepin has recently been ‘rebadged’ as a sleeping tablet (only 50 years too late! But that is psychiatrists’ knowledge of pharmacology for you!). I have been using it as a hypnotic for twenty-five years or so, nice to see people catching up at last. The rationale behind that is explicated in my TCA review paper (free pdf here), see table 6.

It is logical to select a few of the TCAs for antidepressant treatment and familiarise oneself with the use of those. The notes on 'receptor affinities' and 'toxicity' clarify and substantiate the rationale for the following preferences, see the TCA review paper (1).

Clomipramine: is probably still be the best and cheapest serotonin and noradrenalin reuptake inhibitor SNRI (But note recent ‘price gouging’ here [link]).

Nortriptyline: potent as a noradrenalin reuptake inhibitor, modest but useful sedative effect, low anti-muscarinic effect, linear pharmacokinetics, no active metabolites, no significant inhibition of cytochrome P450 enzymes, cheap. Can be safely combined with both an SRI (preferably sertraline and an MAOI: so is a good ‘bridging’ drug.

Amitriptyline: evidence for superior efficacy vs SRIs in severe depression (but many regard clomipramine as a more potent AD).

Imipramine/Desipramine: best side effect vs potency profile (Desipramine), particularly the lowest propensity to cause postural hypotension or anti-muscarinic side effects (note lofepramine (2) is similar and is metabolised into desipramine (3)). But Desipramine is very potent and the usually recommended dose range is very probably much too high (link).

TCAs vs the rest

Selected tricyclic antidepressants remain important and effective first choice (‘first-line’) treatments for major depressive disorder (4). The relatively higher toxicity of some of them in overdose (especially dothiepin-- see ‘toxicity’), and other side effects, persuade some authorities to over-generalise, over-simplify and say they are no-longer suitable for ‘first-line’ treatment in primary care. Nonsense, in the sense of ‘non-sense’. The discontinuation rates due to SEs are not meaningfully different for selected TCAs and newer ADs. Indeed, in my experience patients are less likely to need to cease NTP than SSRIs.

The evidence on toxicity does not logically support the widely advocated, but simplistic, approach of avoiding TCAs because they might have higher toxicity if someone takes an OD. To start with, some TCAs are less toxic than some ‘newer’ drugs (e.g. nortriptyline is less toxic than venlafaxine). Also, note that some 95% of deaths by suicide are not caused by the antidepressant drug prescribed, so prescribing a less toxic drug does not address the main problem of death from suicide attempts. That is especially so if the shiny new drug is, in reality, less effective (which some, perhaps many, of the newer drugs probably are). Indeed, the evidence that some old drugs are more effective than most of the new drugs remains strong-- especially for amitriptyline, imipramine and clomipramine and tranylcypromine, phenelzine isocarboxazid (see other notes).

The risk of suicide, even if that is by over-dose with the prescribed TCA, is minimised by 'good clinical management' (e.g. among other measures, patients should be attending frequently (or be in hospital), only a small (sub-lethal) supply may be issued at each visit, if no responsible person is available to supervise the supply. Remember, 95% of those who die by suicide use means other than the drug they are prescribed.

Misinformed views about SEs and toxicity have caused most doctors to make SSRIs their ‘default’ choice (follow the ‘guidelines’, then you do not have to think for yourself!).

There are good reasons not to use SRIs as ‘first-line’ for some patients (see below), but most doctors are ignorant of what these are, to their patients’ detriment.

When to consider avoiding SRIs as first choice

We can predict which patients are likely to find a TCA to be a more satisfactory option as a first-choice treatment:

Typical "endogenous" symptom profile, or more severe, depressive illness.

Patients with previous episodes of severe depression unresponsive, or partially responsive, to an SSRI).

Those whose current episode is severe or who show psychomotor retardation or lack of energy (optimal choices, imipramine, amitriptyline and clomipramine, my preference is definitely for clomipramine because it is an 'SNRI").

Those with pre-existing history of, or present symptoms of, marked insomnia. Also patients with restless leg syndrome, which is precipitated and exacerbated by SRIs.

Those with previous or present symptoms of gastrointestinal disturbance, reflux, dyspepsia, GI ‘overactivity, GI bleed, or any bleeding tendency or propensity for bruising.

Those with anorexia and weight loss.

Those with present, or past, history of significant suicidal features or attempts. Such patients may be made worse by SSRIs.

Those with high anxiety or agitation.

If concern over cytochrome P450 enzyme drug interactions is relevant. TCAs cause less problems in this area than many new drugs.

A history of hyponatremia.

Any concern regarding discontinuation or withdrawal syndromes should be a cause for caution and careful consideration of alternative strategies.

The above factors, and others, will indicate a TCA may be the optimal first choice.

Gillman's maxim No. 2

The longer a new drug is in use the smaller its side effect advantages turn out to be, compared with previously existing drugs.

I am astonished that others took so long to appreciate the problems caused by SRIs in relation to bleeding, serious GI problems and frequent, almost unavoidable, sexual dysfunction, not to mention interactions caused by CYP450 inhibition.

That demonstrates the power of indoctrination by advertising.

There is evidence from both clinical experience and research that SSRIs noticeably increase the risk of gastric disturbance and bleeds. This is probably for two reasons; they are 'pro-kinetic' in the GI tract (hence the side effect of diarrhoea) and they increase the bleeding time (by depleting platelet 5-HT). It is astonishing that everyone seems to have forgotten so quickly that depletion of platelet 5-HT was the assay initially used indicate whether a drug was an SRI!

A quick point here about ‘side effects’, which is a mis-used term. The main so-called side effects of many drugs, particularly SSRIs, are an inevitable consequence of their main intended mechanism of action, as illustrated by  increased bleeding time caused by depletion of platelet 5-HT, gastric upset, sexual dysfunction. Hence they occur in all subjects, to a greater or lesser degree.

It behoves us all to be sceptical about SEs and alert to the emergence of long-term problems — such problems are still emerging with SSRIs after 30 years! E.g. see (5-7), and most recently the spectre of autism possibly being exacerbated or even caused by SRIs in pregnancy (8, 9). Post marketing surveillance in most countries is a relatively neglected area; we must not expect that side effects will always be obvious.

Sertraline, like nortriptyline, has a particularly favourable pharmacokinetic and side effect profile with a lesser propensity for interactions and is a 1st choice (10). It is also a weak dopamine re-uptake inhibitor and that may confer significant advantage, particularly in relation to the insidious amotivational syndrome that I think is underappreciated as an effect of SRIs (see note on bupropion).

Three of the other selective serotonin reuptake inhibitors have significant and sometimes dangerous interactions, mostly via cytochrome P450 enzymes; these are fluoxetine (2D6 and 3A4), paroxetine (2D6) and fluvoxamine (1A2 and 2C9 /19). For this reason, it is hard to justify their routine use by primary care doctors who are likely to encounter difficulties keeping up with the multiple possible interactions. Some of these interactions have precipitated serious morbidity and have led to expensive litigation.

SSRIs are often an inadequate treatment for more severe depressive illness.

I advise great caution if treating "endogenous" depression with these drugs, one often encounters degrees of improvement that fall well short of full remission of illness. That is unacceptable, because full remission of illness is the goal.

Less effective drugs probably include; moclobemide, citalopram, paroxetine, fluvoxamine, trimipramine, doxepin, dothiepin, trazodone, nefazodone and mianserin and its cousin 6-azamianserin marketed as mirtazapine.

Although the old monoamine oxidase inhibitors (MAOIs), tranylcypromine and phenelzine, are no longer advertised (how many young doctors do not know they even exist?) it is well to remember that they are not just very effective, but are the treatment of choice for some patients.

The therapeutic effectiveness of many new drugs for major depression is not yet satisfactorily established (and probably never will be), yet a large proportion of doctors rush to use the most recently approved drug on the flimsiest of evidence.

References

1.         Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol, 2007. 151(6): p. 737-48.

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707253/pdf

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17471183

2.         Bolden-Watson, C and Richelson, E, Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci., 1993. 52(12): p. 1023-9.

3.         Lancaster, SG and Gonzalez, JP, Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs, 1989. 37(2): p. 123-40.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2649353

4.         Arroll, B, Macgillivray, S, Ogston, S, Reid, I, et al., Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med, 2005. 3(5): p. 449-56.

http://www.ncbi.nlm.nih.gov/pubmed/16189062

5.         Laporte, S, Chapelle, C, Caillet, P, Beyens, MN, et al., Bleeding Risk under Selective Serotonin Reuptake Inhibitor (Ssri) Antidepressants: A Meta-Analysis of Observational Studies. Pharmacol. Res., 2016.

http://www.ncbi.nlm.nih.gov/pubmed/27521835

6.         Jiang, HY, Chen, HZ, Hu, XJ, Yu, ZH, et al., Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2015. 13(1): p. 42-50 e3.

http://www.ncbi.nlm.nih.gov/pubmed/24993365

7.         Anglin, R, Yuan, Y, Moayyedi, P, Tse, F, et al., Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am. J. Gastroenterol., 2014. 109(6): p. 811-9.

http://www.ncbi.nlm.nih.gov/pubmed/24777151

8.         Gentile, S, Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? J Affect Disord, 2015. 182: p. 132-7.

https://www.ncbi.nlm.nih.gov/pubmed/25985383

9.         Clements, CC, Castro, VM, Blumenthal, SR, Rosenfield, HR, et al., Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol. Psychiatry, 2015. 20(6): p. 727-34.

https://www.ncbi.nlm.nih.gov/pubmed/25155880

10.       Cipriani, A, Furukawa, TA, Geddes, JR, Malvini, L, et al., Does randomized evidence support sertraline as first-line antidepressant for adults with acute major depression? A systematic review and meta-analysis. J Clin Psychiatry, 2008.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19026250

It is common for medical researchers, medical professionals and people looking at data on the Internet, to misunderstand receptor affinity data, in relation to both its accuracy and its functional consequences. The extent to which such data is misrepresented in some scientific papers makes it difficult to be certain whether lack of understanding or disingenuousness is at the root of the problem. My web site essay and my published paper (1) on the receptor data in relation to the drug mirtazapine illustrates this point, but similar observations are relevant for the data on many other drugs such as fluoxetine, quetiapine etc.

The first major issue is that it is necessary to compare apples with apples, and not apples with oranges or bananas. What that means in this field of research is using only human cloned receptor (HCR) data. Receptors vary between species and measurements made in test tubes (‘in vitro’) using tissue from rats or other species cannot be compared to what happens at a similar receptor in humans. Some papers mix measurements made in different tissues and in different species, all in the same table of data, without making it clear to the reader what is being done (that is what Organon did with the mirtazapine data, and see also (2)). Lilly did the same with Prozac (fluoxetine) as analysed by Stanford (3). It seems to me that can only be explained by incompetence or dishonesty.

Since the relevant receptors were not produced in their human cloned form until the mid-1990s any paper before then is almost certain to be a mixture of measurements made in different species (with the exception of some work done with human brain post-mortem tissue cf. early papers by Elliott Richelson (4, 5)).

For our present purposes non-HCR values can be dismissed as being insufficiently accurate and not comparable to subsequent data derived from human cloned receptors (HCR) assays. Also note that IC50 data are often of little use because the values are so dependent on assay conditions such as substrate concentration they cannot usually be meaningfully compared.

Affinity is only part of the story and one cannot leap reliably from affinity to potency to efficacy.

My review of the tricyclic antidepressants was the first paper to assemble the HCR data on these drugs and the tables in that paper are thus more precisely comparable for side effects and benefits between drugs than any previous review. Furthermore, that paper also used other types of data to establish a relationship between receptor affinity and magnitude of side-effects, toxic effects and beneficial effects. That is quite a complex process and anyone interested should read that paper carefully. My review in Biological Psychiatry (6) used that approach to look at serotonin toxicity with various different classes of drugs. Indeed it was the understanding resulting from those considerations that led me to make the prediction that methylene blue must be a potent MAOI. That prediction was correct and has been a life-saving revelation for many patients. MB is being used for all sorts of purposes, indeed nearly 10% of Americans are on SSRIs, so many people are at risk of the serious interaction between MB and SRIs.

However, as noted in that BJP paper, it must be remembered that even the best laboratories will get significantly different results with apparently the same techniques. My estimate of the variability in human cloned receptor data measurements made in different laboratories was that they varied by a factor of 10. It is thus clear that any papers that discuss comparisons between drugs and do not take that variability into account are not realistic.

Another characteristic of such papers (e.g. (2, 7)) is that many of them quote results to spurious levels of accuracy. In other words measurements which are only accurate to one decimal place are given to 3 decimal places. The next factor to take into account is that for us to be confident in scientific results they need to be replicated by independent workers. It needs to be shown that the results are within a reasonable degree of agreement. Many of the values being touted for drugs have not been independently replicated (e.g. norquetiapine, aka N-desalkylquetiapine, as an NRI). If we remind ourselves of the approximately tenfold variation in values produced by different laboratories that will help to maintain some degree of objectivity and realism. This variation makes a nonsense of most of the claims about atypical antipsychotics (see separate commentary).

In summary therefore, human cloned receptor (HCR) data is valuable in helping us to understand the potency of drugs for particular receptors but it needs to be interpreted with the above caveats in mind. Even then, we cannot always be sure whether different drugs achieve the same levels in the human brain under every day conditions and there are various other variables to be taken into account. Anyone without in-depth understanding of therapeutics and pharmacology is unlikely to be able to understand the various other factors and variables that are relevant which include the notions of “agonist directed trafficking”, intrinsic activity and binding tightness. There is much we still do not understand about nerve cells and neuro-transmission: indeed the reality and consequences of agonist directed trafficking have only just begun to be recognised.

One of the things that my research has been concerned with, and has clarified, is the relationship between the in vitro (test tube) receptor activities measured in experimental work and the actual effect of drugs in humans. This is a vital consideration because the potency of many of these drugs varies by several orders of magnitude [see table of Receptor Affinity data below]. So, the key question is how potent do these drugs have to be before they have significant actions?

Note that the table below contains a range of values for the receptor affinity measurement. This needs to be taken account of when comparisons are made and it is frequently not valid to try to make precise comparisons. The data has to be interpreted in the light of other data and properties of the drug so that a best guess can be made as to exactly what the data indicates. When reading different papers care needs to be taken to note whether the data relating to human cloned receptor assays is being presented, or some other technique. HCR data is probably the benchmark and all data herein is HCR data unless otherwise indicated.

 

 


Table Human cloned receptor (HCR) data relating to ‘dual action’

Reuptake inhibitor affinities Ki nM (modified PKG March 2010)

Drug

TYR30

NA

5-HT

NA/5-HT

SSRIs (for comparison)

-

>1000

0.1-20

~ 1:1000

Amitriptyline

N/A

19 - 102

2.8 - 36

~1:1.5

Nortriptyline

+++

1.8-21

15-280

Clomipramine

N/A

54

0.14-0.3

~2:1

Desmethylclomipramine*

+++

<1*

-

Imipramine

N/A

20 - 142

1.3 - 20

~1:2

Desipramine

+++

0.63 – 8.6

22 -180

Duloxetine**

0/+

7.5-20

0.8-3.7

~10:1

Venlafaxine**

0/+

1,420–6,300

7.5-145

~200:1

Sibutramine

-

No HCR data

No HCR data

 

Milnacipran**

-

151-200

68-123

~1.7:1

Table Legend TYR30

NA 5-HT NA/5-HT

+++ potent effect ++ moderate + weak 0 no significant effect.

 

 

 

References

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2.                  Gross, G, Xin, X, and Gastpar, M, Trimipramine: pharmacological reevaluation and comparison with clozapine. Neuropharmacology, 1991. 30(11): p. 1159-66.

3.                  Stanford, SC, Prozac: panacea or puzzle? Trends Pharmacol Sci, 1996. 17(4): p. 150-4.

4.                  Richelson, E, Neuroleptic Affinities for Human Brain Receptors and Their Use in Predicting Adverse Effects. J Clin Psychiatry, 1984. 45: p. 0.

5.                  Richelson, E, The Newer Antidepressants:  Structures, Pharmacokinetics, Pharmacodynamics, and proposed Mechanisms of Action. Psychopharmacol. Bull., 1984. 20(2): p. 213-223.

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

7.                  Meltzer, HY and Massey, BW, The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol, 2011. 11(1): p. 59-67.