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Publications

I have published widely in peer reviewed journals, especially in the field of psychopharmacology, particularly concerning serotonin syndrome / serotonin toxicity. Five of my Major reviews have covered various aspects of serotonin toxicity. I have also reviewed and commented on other aspects of adverse drug interactions. 

Recent Scientific Papers by Dr Gillman with Links & Synopsis

[1]    Top W, Gillman PK, de Langen C, Kooy A. Fatal methylene blue associated serotonin toxicity.
2012:[in preparation].

The first report of a fatality from MB and an SRI, in this case venlafaxine


[2]    Gillman PK. Methylene Blue: A Risk for Serotonin Toxicity. Update.
ANZCA Bull. 2012
This is a follow-up to the warning published in this journal in 2008


[3]    Gillman PK. 'Withdrawal neuroleptic malignant syndrome': a phantom explanatory cause for a fatality.
Med Sci Law. 2011 Apr;51:122-3; author reply 4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21793478
This is a criticism of the report in this journal of a supposed death related to a virtually unrecognised (because it doesn't exist) syndrome purported to be related to withdrawal of neuroleptics. It's a good example of poor refereeing of poor case reports which is why the literature on this sort of thing is peppered with misleading misinformation. Again, as is so often the case, the authors response simply doesn't address the issues that were raised.


[4]    Gillman PK. Monoamine oxidase inhibitors, dietary tyramine and drug interactions (V2.3.2).

This review of the tyramine content of foods and drinks is the most detailed, accurate and extensive analysis yet presented on this subject. I have not published this as a peer-reviewed paper, partly because it's too long and complicated and would have to be rewritten and shortened for a journal: I do not have the inclination or time for that. It is the recommended source of information from Stephen Stahl's NEI website. It has also been commended by a number of prominent authorities in the field, some of whom had input at the draft stage, which assisted with completeness and accuracy. It can therefore be regarded as informally 'peer reviewed'.


[5]    Gillman PK. Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors.
J Clin Psychopharmacol. 2011;31:66-74.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21192146
As can be seen from the abstract this review covers mainly theoretical aspects of pharmacology and interactions and other things I have written cover more clinical aspects of MAOI use, viz. various PUN notes


[6]    Gillman PK. CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity.
J Psychopharmacol (Oxf). 2011;25:429-3.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20142303
This is a fascinating story of how the coincidental emergence of the observations and research demonstrating the previously unknown MAOI properties of methylene blue was revealed. This resulted from predictions made by the spectrum concept of serotonin toxicity that I have developed. Again, this paper was partly precipitated, like the triptan paper, by recognition and frustration with the fact that an appropriate understanding of the mechanisms of serotonin toxicity, and how they demonstrate the mechanism of action and potency of various different drugs, was failing to be appreciated by psycho-pharmacologists and others. I would recommend it as a good starting point for anyone who wants to understand serotonin toxicity.


[7]    Finberg J, Gillman P. Pharmacology of MAO-B inhibitors and the cheese reaction. In: Youdim M, Riederer P, eds. Int Rev Neurobiol. Burlington: Elsevier Inc. Academic Press. 2011:169-90.
Comments
This is a co-authored chapter in a major prestigious book dealing with tyramine and the cheese reaction in the context of the new MAOI rasagiline.

[8]    Chapin JW, Megan Chacon MC, Neice A, Gillman PK. Serotonin Toxicity after Administration of Methylene Blue for Vasoplegia.
Anesthesiology. 2011;A1203 October 18:A1203October 18, 20118:00:00 AM - 11:00:00 AMHall A1 South Area A.

Another MB report that I assisted in the publication of.


[9]    Gillman PK. Hyperthermic Fatalities of Uncertain Cause.
Neuropathology. 2010;31: 306–7 (published online: 14 Mar 2011).

Another strange and poor case report


[10]    Gillman PK. Interaction of temperature regulation mechanisms.
Lancet. 2010;376:233-4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20656123
Temperature Regulation Mechanisms, Synergistic Interactions: a Diagnostic Aid?


[11]    Gillman PK. Neuroleptic malignant syndrome: half a century of uncertainty suggests a Chimera.
Pharmacoepidemiol Drug Saf. 2010;19:876-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20665596
This is a substantive commentary on a review article published in the journal previously pointing out a number of problems with the traditional concept and interpretation of NMS


[12]    Gillman PK. Neuroleptic malignant syndrome, poor science and inaccurate measurements.
J Psychopharmacol (Oxf). 2010:20 May 2010, 10.1177/0269881110367461.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20488833
Comment on the poor science and poor refereeing so common in journal Case reports


[13]    Gillman PK. Combining antidepressants: Understanding Drug Interactions is the Sine Qua Non.
Adv Psychiatr Treat. 2010;16:76-8.

This is a commentary on an article published in the Journal of the Royal College of psychiatrists in the UK, which is their in-house journal aimed at keeping specialists up-to-date with recent advances. In my view it illustrates the continuing woeful state of knowledge of pharmacology exhibited even by psychiatrists in academic learning centres. If this was peer-reviewed then its publication is further evidence of the weaknesses of the peer review system.


[14]    Gillman PK. In Reference to Parathyroid Surgery and Methylene Blue: a Review with Guidelines for Safe Intraoperative Use.
Laryngoscope. 2010;120:436-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19950381
Journal article


[15]    Gillman PK. Neuroleptic Malignant Syndrome: Mechanisms, Interactions and Causality.
Mov Disord. 2010;25:1780-90.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20623765
It has frequently been stated that serotonin syndrome and neuroleptic malignant syndrome are similar and easily confused. I have been one of the few voices to express disagreement with this notion and several of my early publications dealt in detail with this issue. Indeed I stated earlier on that the two syndromes were as different as chalk and cheese. I am pleased to say that time and accumulating evidence has persuaded the experienced toxicologists that I know to agree with this position, if they did not already. Because this notion has been so persistent over the last decade I decided that at some stage I would review neuroleptic malignant syndrome itself in an attempt to clarify some issues and lay the groundwork for increasing credibility of my views on these two syndromes. In doing this I came to the view that the causal relationship between neuroleptics and this somewhat ill-defined syndrome does not rest on very sound science, and the evidence of a causal relationship is weak. In my view this should precipitate a different way of thinking about MMS.


[16]    Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium.
J Psychopharmacol (Oxf). 2009 May 7;24:1433-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19423610
As Shakespeare had Edmund say in 'King Lear', "the wheel comes full circle, I am here". This joint paper was written as a result of my request to Clare Stanford to check the details of this previously published case report about possible serotonin toxicity. I contacted her to check these details because this was the only case in the literature that appeared to potentially contradict my prediction about the interaction between methylene blue and SSRIs. The odd coincidence is that I remember Clare asking my opinion about this case when they were originally considering writing it up. The possible significance of methylene blue was not noted, recognised, or reported. When I asked Claire to check the records, without giving away what I was expecting, she quickly understood what was going on because her e-mail replying to my request had the subject line “Sherlock”. The patient had of course been given methylene blue so this case report became yet further evidence.


[17]    Schwiebert C, Irving C, Gillman PK. Small doses of methylene blue, previously considered safe, can precipitate serotonin toxicity.
Anaesthesia. 2009;64:924-.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19604213
Another MB case report I assisted with.


[18]    Gillman PK. Triptans, Serotonin Agonists, and Serotonin Syndrome (Serotonin Toxicity): A Review.
Headache. 2009;50:264-72.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19925619
This major review paper was written with the background of the regulatory agencies in the UK and the USA not appropriately advising doctors about the dangers of serotonin toxicity with types of drugs that were currently in the news around this time. That is to say the anti-migraine drugs, triptans, and the dye called methylene blue, used primarily for parathyroid surgery. The FDA warned of possible fatalities with triptans, when in my view there was no theoretical or clinical reason to do so: contrary-wise, the FDA & MRHA in the UK failed to advise of the risk of serotonin toxicity and possible fatalities (some had actually occurred) despite good, even unassailable, theoretical and clinical evidence that such things were almost certain to occur.


[19]    Gillman PK. Mechanisms, management and measurement in atropine induced hyperthermia.
Anaesth Intensive Care. 2009;37:322-3.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19400503


[20]    Gillman PK. Methylene blue is a potent monoamine oxidase inhibitor.
Can J Anaesth. 2008 May;55:311-2.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18451123
This is a comment on a short paper published previously in this journal about methylene blue which may have given some readers, who were not intimately familiar with the literature, the impression of being an original contribution.


[21]    Gillman PK. Methylene Blue: A Risk for Serotonin Toxicity.
ANZCA Bull. 2008;17:36.



[22]    Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.
Br J Pharmacol. 2007;152:946-51.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17721552
As soon as I formed the view, back in 2006, that methylene blue must be a monoamine oxidase inhibitor, I decided that evidence to establish that, using the most appropriate modern techniques, was highly desirable. I therefore contacted Rona Ramsay at St Andrews, because she had high credibility and expertise in this area. She was sufficiently impressed by the idea to scratch around and create the time and money to actually do the work. We established that MB is a very potent inhibitor of MAO A, in vitro, with a Ki of 27 nM and that it binds in the active site of MAO A.


[23]    Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated.
Br J Pharmacol. 2007;151:737-48.
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
The abstract is self-explanatory. It has long been my view that the new and heavily advertised drugs were being used more frequently than the scientific evidence justified. I therefore always wanted to do a review of the old trycyclics to try to counterbalance the distorted literature. An experienced and widely respected professor in this field suggested that the paper was of sufficient merit to be offered to the most prestigious and respected journals. I therefore offered it to the British Journal Pharmacology. The initial two referees reports basically had no significant adverse criticisms of the material, but suggested to the editor that since these drugs were of little use and past history such a review was pointless!. I wrote a robust response to those comments to the editor and, much to his credit, he appreciated the validity of the points I made and sent the paper about to new referees who endorsed it enthusiastically. The rest, as they say, is history. I was very proud to receive an e-mail from the Journal at the end of 2007 telling me the paper had been downloaded 1,715 times, which was more than any other paper in that issue of the journal. It has subsequently notched up a high citation index and has now been quoted more than any other paper in this field.


[24]    Peterson G, Jackson S, Naunton M, Gillman PK. Beware of anticholinergics in the elderly: delirious dangers of the deadly nightshade.
J Pharm. 2006;25:882-4.

It has long been my clinical experience, and my interpretation of the pharmacological literature, that the memory impairing and delirium inducing propensity of drugs with anticholinergic properties have been under recognised and underestimated. Therefore when I was asked to assist with a little help for this review I was very pleased to do so.


[25]    Lawrence KR, Adra M, Gillman PK. Serotonin Toxicity Associated with the Use of Linezolid: A Review of Postmarketing Data.
Clin Infect Dis. 2006;42:1578-83.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16652315
I made a small contribution to this original paper looking at the possibility of ST with the antibiotic linezolid.


[26]    Gillman PK. Methylene Blue implicated in potentially fatal serotonin toxicity.
Anaesthesia. 2006;61:1013-4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16978328
This was the initial brief report postulating that methylene toxicity was serotonin toxicity resulting from the fact that methylene blue was a monoamine oxidase inhibitor


[27]    Gillman PK. Extracting value from case reports: lessons from serotonin toxicity.
Anaesthesia. 2006;61:419-22.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16674612
This was an editorial explaining about serotonin toxicity and methylene blue at the time the first three or four reports were recognised.


[28]    Gillman PK. A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status.
Hum Psychopharmacol. 2006;21:117-25.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16342227
There is an essay on my website telling the story of the misunderstood pharmacological data about Mirtazapine. This drug is almost identical (pharmacologically) to a previously patented drug by the same company which was introduced in the 1970s and called mianserin. The production of similar drugs like this has sometimes been referred to as “badge engineering”. Both these drugs are extremely potent antihistamines which means they cause sedation and weight gain but their value as antidepressants remains debatable. In my experience I have rarely or never seen a convincing antidepressant response in patients suffering severe endogenous depression. The paper argues that these drugs have no significant monoamine reuptake inhibitor capacity and no other plausible antidepressant mechanism of action and particularly that they have no significant serotonergic action and are unable to precipitate serotonin toxicity. Subsequent work has endorsed most of those views. Animal models of serotonin toxicity clearly demonstrate that mirtazapine reduces the severity of the syndrome in an animal model; it does not exacerbate it. That would appear to prove conclusively that it is essentially an anti-serotonergic drug, not a pro-serotonergic drug.


[29]    Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.
Biol Psychiatry. 2006;59:1046-51.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16460699
This major review paper is one I had wanted to write for a long time because it seemed to me that an understanding interactions causing serotonin toxicity produces useful insights into the clinically meaningful pharmacological potency/effects of many different drugs. This is something which still seems to be insufficiently appreciated. However, the paper is steadily attracting more and more citations, so the message may be getting across.


[30]    Gillman PK. Drug interactions and fluoxetine: a commentary from a clinician’s perspective.
Ex Op Drug Saf. 2005;4:965-9.



[31]    Gillman PK. More misleading case reports.
Anaesthesia. 2005:http://www.anaesthesiacorrespondence.com/Correspond3.asp?articleid=4345&archive=.
http://www.anaesthesiacorrespondence.com/Correspond3.asp?articleid=4345&archive=


[32]    Gillman PK. Understanding toxidromes: serotonin toxicity. A commentary on Montanes-Rada et al.
J Clin Psychopharmacol. 2005;25:625-6.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16282860
This was an attempt to correct misconceptions about neuroleptic malignant syndrome and serotonin toxicity and clarify some aspects of the definition of toxidromes. This is something that psychiatrists seem to be struggling to understand.


[33]    Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
Br J Anaesth. 2005;95:434-41.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16051647
The nature of the interaction between opioid analgesics and trycyclics depressants and serotonin reuptake inhibitors is something that has been misunderstood ever since the discovery of these drugs in the 1950s. Many texts confuse different forms of toxicity and contained incomplete information which can be misleading, especially in the context of more recent discoveries and interpretations. Unfortunately, more than five years down the track many sources still contain information that is incomplete and misleading. Review therefore aimed to explain and clarify these issues.


[34]    Gillman PK, Whyte IM. Serotonin syndrome. In: Haddad P, Dursun S, Deakin B, eds. Adverse Syndromes and Psychiatric Drugs. Oxford: Oxford University Press 2004:37-49.
Comments
Book chapter

[35]    Gillman PK. Re: no evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline.
Hum Psychopharmacol. 2004 Dec 21;20:61-2.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15614840
0885-6222
Journal article


[36]    Gillman PK. Making sense of serotonin toxicity reports. A comment on Chopra et al.
World Journal of Biological Psychiatry. 2004;5:166-7.



[37]    Gillman PK. Moclobemide and the risk of serotonin toxicity (or serotonin syndrome).
CNS Drug Rev. 2004;10:83-5.

This is a fairly long commentary in response to a review paper about moclobemide. My view is in accordance with a number of other experienced psycho-pharmacologists of my acquaintance and is: I regard moclobemide as an ineffective antidepressant, and undoubtedly much less effective than the old irreversible MAOIs like tranylcypromine. However, mixing moclobemide with SSRIs is potentially risky and everyone who tried doing it back in the early days has become strangely silent, and not responded to enquiries about their experience. The only exception to that is Doctor Hawley, who did more work on this than anyone else, as far as I know. I have quoted his comments elsewhere, but he stopped doing it because of the high frequency of occurrence moderately severe serotonergic effects, and one or two cases of actual serotonin toxicity. It is a delicate pharmacological balancing trick which is probably not safely attainable in everyday practice.